Pharmaceutical compounds

ABSTRACT

Diketopiperazines of the formula: ##STR1## where each of R 1  to R 10 , which may be the same or different, is independently selected from the group consisting of hydrogen, C 1  -C 6  alkyl unsubstituted or substituted by one or more halogen atoms, C 1  -C 6  alkoxy, C 1  -C 6  alkylthio, halogen, hydroxy, nitro, phenyl, -cyano, --CH 2  OH, --CH 2  COOH, --CO 2  R 11 , --NHCOR 11 , --NHSO 2  R 13 , --SO 2  R 13 , --CON(R 11  R 12 ), --SOR 13 , --SO 2  N(R 11  R 12 ), --N(R 11  R 12 ), and --O(CH 2 ) n  N(R 11  R 12 ), --O(CH 2 ) n  CO 2  R 11 , --OCOR 11 , --CH 2  OCOR 11 , --CH 2  NHCOR 11 , --CH 2  NHCOOR 13 , --CH 2  SR 11 , --CH 2  SCOR 11 , --CH 2  S(O) m  R 13  wherein m is 1 or 2, --CH 2  NHCO(CH 2 ) n  CO 2  R 11 , --N(R 11 )COR 12 , --NHCOCF 3 , --NHCO(CH 2 ) n  CO 2  R 11 , --NHCO(CH 2 ) n  OCOR 11  and --NHCO(CH 2 ) n  OR 11  wherein n is 0 or is an integer of from 1 to 6, each of R 11  and R 12  is independently H or C 1  -C 6  alkyl and R 13  is C 1  -C 6  alkyl; or any of R 1  and R 2 , R 2  and R 3 , R 3  and R 4  and R 4  and R 5 , or R 6  and R 7 , R 7  and R 8 , R 8  and R 9  and R 9  and R 10 , form together with the carbon atoms to which they are attached a benzene ring; and pharmaceutically acceptable salts and esters thereof are inhibitors of the plasminogen activator inhibitor.

This application is a 35 USC 371 of PCT/GB93/01734 filed Aug. 6, 1993.

The present invention relates to compounds useful as inhibitors of plasminogen activator inhibitor (PAI), to their preparation and to pharmaceutical and veterinary compositions containing them.

Plasminogen activators (PAs) are serine proteases which control the activation of the zymogen, plasminogen, to the active enzyme plasmin. Plasmin is important in a number of physiological and pathological processes including fibrinolysis, tissue remodelling, tumour growth and metastasis. The glycoprotein plasminogen activator inhibitor (PAI) is an endogenous fast-acting inhibitor of PA activity. PAI is a member of the serpin family and is synthesised by a variety of cells including endothelial cells. An imbalance between PAs and PAI contributes to a number of pathological conditions including haemostasis, inflammation, tumour growth and metastasis.

The present invention provides the use of a diketopiperazine of formula (A): ##STR2## wherein each of R₁ to R₁₀, which may be the same or different, is independently selected from hydrogen, C₁ -C₆ alkyl unsubstituted or substituted by one or more halogen atoms, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, halogen, hydroxy, nitro, optionally substituted phenyl, cyano, --CH₂ OH, --CH₂ COOH, --CO₂ R¹¹, --NHCOR¹¹, --NHSO₂ R¹³, --SO₂ R¹³, --CON(R¹¹ R¹²), --SOR¹³, --SO₂ N(R¹¹ R¹²), --N(R¹¹ R¹²), --O(CH₂)_(n) N(R¹¹ R¹²), --O(CH₂)_(n) CO₂ R¹¹, --OCOR¹¹, --CH₂ OCOR¹¹, --CH₂ NHCOR¹¹, --CH₂ NHCOOR¹³, --CH₂ SR¹¹, --CH₂ SCOR¹¹, --CH₂ S(O)_(m) R¹³ wherein m is 1 or 2, --CH₂ NHCO(CH₂)_(n) CO₂ R¹¹, --N(R¹¹)COR¹², --NHCOCF₃, --NHCO(CH₂)_(n) CO₂ R¹¹, --NHCO(CH₂)_(n) OCOR¹¹ and --NHCO(CH₂)_(n) OR¹¹ wherein n is 0 or is an integer of from 1 to 6, each of R¹¹ and R¹² is independently H or C₁ -C₆ alkyl and R¹³ is C₁ -C₆ alkyl; or any of R₁ and R₂, R₂ and R₃, R₃ and R₄ and R₄ and R₅, or R₆ and R₇, R₇ and R₈, R₈ and R₉ and R₉ and R₁₀, form together with the carbon atoms to which they are attached a benzene ring which is optionally substituted; or a pharmaceutically acceptable salt or ester thereof; in the manufacture of a medicament for use as an inhibitor of plasminogen activator inhibitor.

The numerals 1 to 10 denote ring positions on the phenyl groups in formula A. The letters a and b refer to the two phenyl rings themselves.

When any two adjacent groups of R₁ to R₁₀ form, together with the carbon atoms to which they are attached, a benzene ring, that ring is either unsubstituted or it may be substituted by any of the options specified above for R₁ to R₁₀. The benzene ring forms, together with ring a or b respectively, an optionally substituted naphthalene ring structure.

When ring a or b is substituted phenyl, the benzene ring may be substituted at any of the ortho, meta and para positions by one or more substituents, for example one, two or three substituents, which may be the same or different, independently selected from the groups specified above for R₁ to R₁₀ other than hydrogen.

A C₁ -C₆ alkyl group is typically a C₁ -C₄ alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A halogen is, for example, fluorine, chlorine, bromine or iodine. A C₁ -C₆ alkyl group substituted by halogen may be substituted by 1, 2 or 3 halogen atoms. It may be a perhaloalkyl group, for example trifluoromethyl.

A C₁ -C₆ alkoxy group is typically a C₁ -C₄ alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C₁ -C₆ alkylthio group is typically a C₁ -C₄ alkylthio group, for example methylthio, ethylthio, propylthio, i-propylthio, n-butylthio, sec-butylthio or tert-butylthio.

In compounds of formula A free rotation may occur at room temperature about the single bonds connecting rings a and b to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring. Positions 2 and 6, and positions 3 and 5, in both rings a and b can therefore be considered as equivalent. As a consequence the following pairs of substituents can be viewed as interchangeable: R₁ and R₅ ; R₂ and R₄ ; R₆ and R₁₀ ; and R₇ and R₉.

Preferably one of rings a and b is unsubstituted or is mono-substituted whilst the other ring is unsubstituted or is substituted at one or more of positions 2 to 6. The ring which is mono-substituted may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4. Thus for instance, when ring b is mono-substituted, one of R₆ to R₁₀ is other than hydrogen, preferably R₇ or R₈, especially R₈. When ring a is mono-substituted, one of R₁ to R₅ is other than hydrogen, preferably R₂ or R₃, especially R₃. When one of rings a and b is mono-substituted the substituent R₁ to R₅, or R₆ to R₁₀ respectively, is preferably selected from a halogen, for instance fluorine; an alkoxy group, for instance OMe; and an acetamido group --NHAc in which Ac denotes acetyl.

When one of rings a and b is unsubstituted, or is mono-substituted as described in the above paragraph, the other ring may bear any desired substitution pattern. For instance, the other ring may be unsubstituted or may be mono-, di- or tri-substituted at any of positions 2 to 6.

The said other ring may, for instance, be mono-substituted at any of positions 2 to 6. It may also be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or 3,4,5-trisubstituted. Thus, when the said other ring is a and is mono-substituted, four of R₁ to R₅ are hydrogen and one is other than hydrogen. When the said other ring is ring a and is disubstituted, three of R₁ to R₅ are hydrogen and two are other than hydrogen. For example R₁ and R₂, or R₁ and R₃, or R₁ and R₄, or R₁ and R₅, or R₂ and R₃, or R₂ and R₄ are other than hydrogen whilst, in each case, the other three of R₁ to R₅ are hydrogen.

When the said other ring in ring a and is trisubstituted, two of R₁ to R₅ are hydrogen and three are other than hydrogen. For example, R₁, R₂ and R₃, or R₁, R₂ and R₄, or R₁, R₂ and R₅, or R₂, R₃ and R₄ are other than hydrogen whilst, in each case, the other two of R₁ to R₅ are hydrogen.

When the said ring is b and is mono-substituted, four of R₆ to R₁₀ are hydrogen and one is other than hydrogen. When the said other ring is b and is di-substituted, three of R₆ to R₁₀ are hydrogen and two are other than hydrogen. For example R₆ and R₇, or R₆ and R₈, or R₆ and R₉, or R₆ and R₁₀, or R₇ and R₈, or R₇ and R₉, are other than hydrogen whilst, in each case, the other three of R₆ to R₁₀ are hydrogen. When the said other ring is b and is trisubstituted, two of R₆ to R₁₀ are hydrogen and three are other than hydrogen. For example R₆, R₇ and R₈, or R₆, R₇ and R₉, or R₆, R₇ and R₁₀, or R₇, R₈ and R₉ are other than hydrogen whilst, in each case, the other two of R₆ to R₁₀ are hydrogen.

Alternatively, any two adjacent substituents in the said other ring may, together with the carbon atoms to which they are attached, complete a second benzene ring which is optionally substituted, thus forming an optionally substituted naphthyl group with the said other ring. For instance, in ring a R₁ and R₂, or R₂ and R₃ may form together with carbon atoms 2 and 3, or 3 and 4 respectively, an optionally substituted benzene ring which, in turn, forms with ring a a naphthyl group which is unsubstituted or substituted by one or more groups specified above for R₁ to R₁₀. In ring b R₆ and R₇, or R₇ and R₈ may form, together with carbon atoms 2 and 3 or 3 and 4 respectively, an optionally substituted benzene ring which, in turn, forms with ring b a naphthyl group which is unsubstituted or substituted by one or more groups specified above for R₁ to R₁₀. Typically the naphthyl group in either case is unsubstituted or is monosubstituted at position 1,2,3 or 4 of the naphthalene ring structure, especially position 4. For example R₁ and R₂ together with ring a, or R₆ and R₇ with ring b, form a 4-dimethylamino-1-naphthyl group.

In a preferred series of compounds of formula A each of R₆ to R₁₀ is hydrogen. In another preferred series of compounds, one of R₆ to R₁₀ is selected from alkoxy, NHCOR¹¹ and halogen and the other four of R₆ to R₁₀ are H. Alkoxy may be, for instance, OMe or OBu^(n). NHCOR¹¹ is typically --NHAc. Halogen is typically F or Cl. Preferably R₈ is alkoxy, especially OMe or OBu^(n) ; NHCOR¹¹, especially --NHAc; or halogen, especially F or Cl; and each of R₆, R₇, R₉ and R₁₀ is H.

In the above-mentioned series of preferred compounds R₁ to R₅ are all hydrogen, or one or two of R₁ to R₅ are other than hydrogen whilst the others are hydrogen. For instance one of R₁, R₂ and R₃ is other than hydrogen. Alternatively R₁ and R₃, or R₂ and R₃, are other than hydrogen. Preferred values for the one or two of R₁ to R₅ which is or are other than hydrogen include alkoxy such as OMe or OBu^(n), halogen such as Cl or F, hydroxy, --N(R¹¹ R¹²), --CO₂ R¹¹, --CH₂ SCOR¹³, --CH₂ SR¹¹, --NHCOR¹¹, --O(CH₂)_(n) N(R¹¹ R¹²), --O(CH₂)_(n) CO₂ R¹¹, --CH₂ NHCO(CH₂)_(n) CO₂ R¹¹, --NHCOCH₂ OR¹¹, --NHCO(CH₂)_(n) OCOR¹¹, --CH₂ NHCOOR¹³ and CF₃. It is also preferred for R₁ and R₂, R₂ and R₃, R₃ and R₄ or R₄ and R₅ to form, together with the carbon atoms to which they are attached, a benzene ring.

Particularly preferred compounds are those wherein R₆, R₇, R₉ and R₁₀ are each H, R₈ is selected from H, OMe and --NHAc and each of R₁ to R₅ is as specified above. In these preferred compounds R¹ to R⁵ are preferably each independently selected from H, halogen, hydroxy, C₁ -C₆ alkoxy, nitro, --CH₂ SCOR¹¹, --CH₂ SR¹¹, --CO₂ R¹¹, --OCOR¹³, CF₃, --O(CH₂)_(n) N(R¹¹ R¹²), --O(CH₂)_(n) CO₂ R¹¹, --CH₂ NHCO(CH₂)_(n) CO₂ R¹¹, --NHCO(CH₂)_(n) OR¹¹, --N(R¹¹ R¹²), --NHCO(CH₂)_(n) OCOR¹¹, --NHCO(CH₂)_(n) CO₂ R¹¹ and --CH₂ NHCO₂ R¹³ or R₁ and R₂, R₂ and R₃, R₃ and R₄, or R₄ and R₅, form with the carbon atoms to which they are attached an optionally substituted benzene ring. Still more preferably, R₁ and R₂ are independently H, nitro or halogen, R₃ is H, hydroxy, --O(CH₂)_(n) N(R¹¹ R¹²), --OCOR¹¹, --O(CH₂)_(n) CO₂ R¹¹, --CH₂ NHCO(CH₂)_(n) CO₂ R¹¹, C₁ -C₆ alkoxy, --NHCO(CH₂)_(n) OR¹¹, --NHCO(CH₂)_(n) OCOR¹¹, --N(R¹¹ R¹²), --CH₂ NHCO₂ R¹³, --CH₂ SR¹¹ or --NHCOR¹¹ ; R₄ is H, halogen, C₁ -C₆ alkoxy, --CH₂ SCOR¹¹, --CH₂ SR¹¹ or --CO₂ R¹¹ ; and R₅ is H, nitro or halogen; or R² and R₃, R₃ and R₄ or R₄ and R₅ form, together with the carbon atoms to which they are attached, an optionally substituted benzene ring.

In one embodiment R₈ is NHAc, each of R₆, R₇, R₉ and R₁₀ is H; R₁ is H or halogen such as Cl or F; R₂ is H, R₃ is halogen such as F or Cl, C₁ -C₆ alkoxy such as OMe, --N(R¹¹ R¹²) such as NMe₂ or --NHCOOR¹³ such as --NHCOOBu^(t) ; R₄ is H and R₅ is halogen such as F, Cl, Br, or is CF₃.

In a second embodiment R₈ is OMe, each of R₆, R₇, R₉ and R₁₀ is H; R¹ is H, nitro or halogen such as Cl; R² is H; R₃ is H, hydroxy, --OCOR¹¹ such as OAc, --NHCO(CH₂)_(n) OCOR¹¹ such as --NHCOCH₂ OAc or --NHCOCH₂ OR¹¹ such as --NHCOCH₂ OH; R₄ is H and R₅ is H or halogen such as F or Cl; or R₂ and R₃ form a benzene ring together with the carbon atoms to which they are attached.

In a third embodiment each of R₁, R₆, R₇, R₈, R₉ and R₁₀ is H; R₂ is H and R₃ is --CH₂ SR¹¹ such as --CH₂ SMe, --CH₂ SCOR¹¹ such as --CH₂ SAc, --NHCO(CH₂)_(n) CO₂ R¹¹ such as --NHCO(CH₂)₃ CO₂ Me, --O(CH₂)_(n) CO₂ R¹¹ such as --O(CH₂)₄ CO₂ H, --O(CH₂)N(R¹¹ R¹²) such as --O(CH₂)₃ --NMe₂, or --N(R¹¹ R¹²) such as --NMe₂ or R₂ is --CH₂ SCOR¹³ such as --CH₂ SAc or --CH₂ SR¹¹ such as --CH₂ SH and R₃ is H; and R₄ and R₅ are both H or both form, together with the carbon atoms to which they are attached, a benzene ring.

In one embodiment of the invention the compound of formula A is the following compound 3: ##STR3##

Certain diketopiperazines have been disclosed as having utility as bioactive agents. Yokoi et al in J. Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity relationship studies on a series of diketopiperazines related to neihumicin, a compound obtained from the micro-organism Micromonospora neihuensis. Kamei et al in J. Antibiotics vol XLIII No. 8, 1018-1020 disclose that two diketopiperazines, designated piperafizines A and B, have utility as potentiators of the cytotoxicity of vincristine.

General formula A embraces diketopiperazines which are novel. Accordingly, the present invention provides a diketopiperazine of formula (A) as defined above, or a pharmaceutically acceptable salt or ester thereof; with the exception of compounds wherein:

(i) each of R₁ to R₁₀ is H;

(ii) R₁ and R₆ are both Cl and the rest of R₂ to R₁₀ are H; R₂ and R₇ are both Cl and the rest of R₁ to R₁₀ are H; R₃ and R₈ are both Me and the rest of R₁ to R₁₀ are H; R₂, R₅, R₇ and R₁₀ are all Me and the rest of R₁ to R₁₀ are H; R₂, R₃, R₄, R₇, R₈ and R₉ are all OMe and R₁, R₅, R₆ and R₁₀ are H;

(iii) R₈ is OMe and the rest of R₁ to R₁₀ are H; and

(iv) 3-p-nitrobenzylidene-6-benzylidene-2,5-piperazinedione and 3,6-di-p-nitrobenzylidene-2,5-piperazinedione.

Examples of specific compounds of formula A are as follows. The compound numbering is adhered to in the rest of the specification:

(3Z,6Z,)-6-benylidene-3-(4-methoxybenzylidene)-2,5-piperazinedione (compound 3)

(3Z,6Z)-6-Benzylidene-3-(2,6-dichlorobenzylidene)-2,5-piperazinedione (compound 21)

(3Z,6Z)-3-(4-Acetoxybenzylidene)-6-benzylidene-2,5-piperazinedione (compound 23)

(3Z,6Z)-6-Benzylidene-3-(4-nitrobenzylidene)-2,5-piperazinedione (compound 74)

3,6-Dibenzylidene-2,5-piperazinedione (compound 22) (mixture of isomers)

(3Z,6Z)-6-Benzylidene-3-(3-nitrobenzylidene)-2,5-piperazinedione (compound 24)

(3Z,6Z)-6-Benzylidene-3-(2-nitrobenzylidene)-2,5-piperazinedione (compound 65)

(3Z,6Z)-6-Benzylidene-3-(4-ethoxybenzylidene)-2,5-piperazinedione (compound 25)

(3Z,6Z)-6-Benzylidene-3-(4-cyanobenzylidene)-2,5-piperazinedione (compound 105)

(3Z,6Z)-3-(4-Aminobenzylidene)-6-benzylidene-2,5-piperazinedione (compound 30)

(3Z,6Z)-3-(3-Acetoxybenzylidene)-6-benzylidene-2,5-piperazinedione (compound 31)

(3Z,6Z)-3-(2-Acetoxybenzylidene)-6-benzylidene-2,5-piperazinedione (compound 32)

(3Z,6Z)-6-Benzylidene-3-(3-hydroxybenzylidene)-2,5-piperazinedione (compound 33)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-benzylidene-2,5-piperazinedione (compound 34)

(3Z,6Z)-3-(2-Acetamidobenzylidene)-6-benzylidene-2,5-piperazinedione (compound 38)

(3Z,6Z)-3-(2-Aminobenzylidene)-6-benzylidene-2,5-piperazinedione (compound 39)

(3Z,6Z)-3-(4-Acetoxymethylbenzylidene)-6-benzylidene-2,5-piperazinedione (compound 43)

(3Z,6Z)-3-(4-Acetamidomethylbenzylidene)-6-benzylidene-2,5-piperazinedione (compound 44)

(3Z,6Z)-3,6-Dibenzylidene-2,5-piperazinedione (compound 45)

(3Z,6Z)-6-Benzylidene-3-(4-butoxybenzylidene)-2,5-piperazinedione (compound 48)

(3Z,6Z)-6-Benzylidene-3-(4-tert-butylbenzylidene)-2,5-piperazinedione (compound 51)

(3Z,6Z)-6-Benzylidene-3-(4-isopropoxybenzylidene)-2,5-piperazinedione (compound 52)

(3Z,6Z)-6-Benzylidene-3-(2,4-difluorobenzylidene)-2,5-piperazinedione (compound 54)

(3Z,6Z)-6-Benzylidene-3-(2-bromobenzylidene)-2,5-piperazinedione (compound 55)

(3Z,6Z)-6-Benzylidene-3-(4-methylthiomethylbenzylidene)-2,5-piperazinedione (compound 59)

(3Z,6Z)-6-Benzylidene-3-(3-thioacetoxymethylbenzylidene)-2,5-piperazinedione (compound 61)

3-((3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene)methylbenzoic acid, methyl ester (compound 62)

(3Z,6Z)-6-Benzylidene-3-(3-mercaptomethylbenzylidene)-2,5-piperazinedione (compound 64)

(3Z,6Z)-6-Benzylidene-3-(4-tert-butoxycarbonylaminobenzylidene)-2,5-piperazinedione (compound 66)

(3Z,6Z)-6-Benzylidene-3-(4-(3-N,N-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione (compound 75)

(3Z,6Z)-6-Benzylidene-3-(4-thioacetoxymethylbenzylidene)-2,5-piperazinedione (compound 76)

(3Z,6Z)-6-Benzylidene-3-(2-chloro-4-hydroxybenzylidene)-2,5-piperazinedione (compound 85)

(3Z,6Z)-6-Benzylidene-3-(3,4-dimethoxybenzylidene)-2,5-piperazinedione (compound 90)

4- (3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene!methylphenoxyacetic acid, methyl ester (compound 93)

4-(4- (3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene!methylbenzylcarbamoyl) butanoic acid, methyl ester (compound 94)

4-(4-((3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene)methylbenzylcarbamoyl)pentanoic acid, methyl ester (compound 95)

5- 4-((3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene)methylphenoxy!pentanoic acid, methyl ester (compound 96)

5- 4-((3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene)methylphenoxy!pentanoic acid (compound 97)

(3Z,6Z)-6-Benzylidene-3-(4-(2-N,N-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione, hydrochloride (compound 99)

(3Z,6Z)-6-Benzylidene-3-(4-(2-N,N-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione (compound 102)

4- (3Z,6Z)-6-Benzylidene-2,5-dioxopiperazin-3-ylidene!methylphenoxyacetic acid (compound 101)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 26)

(3Z,6Z)-6-(4-Methoxybenzylidene)-3-(2-nitrobenzylidene)-2,5-piperazinedione (compound 28)

(3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 29)

(3Z,6Z)-3-(4-Hydroxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 36)

(3Z,6Z)-3-(4-Acetoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 37)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-N-methylacetamidobenzylidene)-2,5-piperazinedione (compound 41)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-methylsulfonylbenzylidene)-2,5-piperazinedione (compound 46)

(3Z,6Z)-3-(4-Butoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 47)

(3Z,6Z)-3-(4-isopropoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 49)

(3Z,6Z)-3-(4-methoxybenzylidene)-6-(4-tert-butylbenzylidene)-2,5-piperazinedione (compound 50)

(3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 53)

(3Z,6Z)-(4-Methoxybenzylidene)-6-(4-tert-butoxycarbonylaminomethylbenzylidene)-2,5-piperazinedione (compound 56)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-methylthiomethylbenzylidene)-2,5-piperazinedione (compound 57)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-methylsulfonylmethylbenzylidene)-2,5-piperazinedione (compound 60)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-thioacetoxymethylbenzylidene)-2,5-piperazinedione (compound 63)

(3Z,6Z)-3-(4-Aminomethylbenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 67)

(3Z,6Z)-3-(2,4-Difluorobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 69)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(2-trifluoromethylbenzylidene)-2,5-piperazinedione (compound 70)

(3Z,6Z)-3-(2,4-Dimethoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 73)

4- (3Z,6Z)-6-(4-Methoxybenzylidene)-2,5-dioxopiperazin-3-ylidene!methylbenzamide (compound 80)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-trimethylacetoxybenzylidene)-2,5-piperazinedione (compound 81)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(4-methoxycarbonylaminobenzylidene)-2,5-piperazinedione (compound 83)

(3Z,6Z)-3-(2-Chloro-4-hydroxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 84)

(3Z,6Z)-3-(4-Acetoxyacetylaminobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 87)

(3Z,6Z)-3-(3,4-Dimethoxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 91)

4-((3Z,6Z)-6-(4-Methoxybenzylidene)-2,5-dioxopiperazin-3-ylidene)-4-methylbenzylcarbamoyl)butanoic acid, methyl ester (compound 100)

(3Z,6Z)-3-(4-Methoxybenzylidene)-6-(2-naphthylmethylene)-2,5-piperazinedione (compound 27)

(3Z,6Z)-3-(4-Hydroxyacetylaminobenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione (compound 88)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-benzylidene-2,5-piperazinedione (compound 34)

(3Z,6Z)-3,6-Di-(3-Nitrobenzylidene)-2,5-piperazinedione (compound 35)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(2,6-dichlorobenzylidene)-2,5-piperazinedione (compound 40)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-chlorobenzylidene)-2,5-piperazinedione (compound 42)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-acetoxymethylbenzylidene)-2,5-piperazinedione (compound 58)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(2-fluorobenzylidene)-2,5-piperazinedione (compound 71)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-fluorobenzylidene)-2,5-piperazinedione (compound 72)

(3Z,6Z)-6-(Benzylidene)-3-(2,4-difluorobenzylidene)-2,5-piperazinedione (compound 76)

(3Z,6Z)-6-(4-Acetamidobenzylidene)-3-(2-trifluoromethylbenzylidene)-2,5-piperazinedione (compound 78)

(3Z,6Z)-6-(4-Acetamidobenzylidene)-3-(2-bromobenzylidene)-2,5-piperazinedione (compound 79)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-trimethylacetoxybenzylidene)-2,5-piperazinedione (compound 82)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-dimethylaminobenzylidene)-2,5-piperazinedione (compound 86)

(3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-tert-butoxycarbonylaminomethylbenzylidene)-2,5-piperazinedione (compound 68)

Compounds of formula A, both known and novel, may be prepared by a process which comprises either (i) condensing compound of formula (I) ##STR4## wherein R₆ to R₁₀ are as defined above and are optionally protected, with a compound of formula (II): ##STR5## wherein R₁ to R₅ are defined above and are optionally protected, in the presence of a base in an organic solvent; or (ii) condensing a compound of formula (I'): ##STR6## wherein R₁ to R₅ are as defined above and are optionally protected, with a compound of formula (III): ##STR7## wherein R₆ to R₁₀ are as defined above and are optionally protected, in the presence of a base in an organic solvent; and, in either case (i) or (ii), if required, removing optionally present protecting groups and/or, if desired, converting one compound of formula A into another compound of formula A, and/or, if desired, converting a compound of formula A into a pharmaceutically acceptable salt or ester thereof, and/or, if desired, converting a salt or ester into a free compound, and/or, if desired, separating a mixture of isomers of compounds of formula A into the single isomers.

A compound of formula A produced directly by the condensation reaction between (I) and (II) or (I') and (III) may be modified, if desired, by converting one or more of groups R₁ to R₁₀ into different groups R₁ to R₁₀. These optional conversions may be carried out by methods known in themselves. For example, a compound of formula A in which one or more of R₁ to R₁₀ is an ester group may be converted to a compound of formula A wherein the corresponding substituent is a free --COOH group, by acid or alkaline hydrolysis at a suitable temperature, for example from ambient temperature to 100° C.

A compound of formula A in which one or more of R₁ to R₁₀ is a --CO₂ H group may be converted into a compound of formula A wherein the corresponding substituent is esterified by esterification, for example by treating the carboxylic acid with a suitable C₁ -C₆ alkyl alcohol in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.

A compound of formula A in which one or more of R₁ to R₁₀ is a free --CO₂ H group may be converted into a compound of formula A in which the corresponding substituent is a group --CON(R¹¹ R¹²), wherein R¹¹ and R.sup. are as defined above, for example by treatment with ammonia or an amine in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.

A compound of formula A in which one or more of R₁ to R₁₀ is a free --CO₂ H group may be converted into a compound of formula A wherein the corresponding substituent is a --CH₂ OH group by reduction, for example using borane in a suitable solvent such as tetrahydrofuran.

A compound of formula A in which one or more of R₁ to R₁₀ is a nitro group may be converted into a compound of formula A in which the corresponding substituent is an amino group by reduction under standard conditions, for example by catalytic hydrogenation.

Protecting groups for R₁ to R₁₀ in any of the compounds of formulae (I), (I'), (II) and (III) are optionally introduced prior to step (i) or step (ii) when any of groups R₁ to R₁₀ are groups which are sensitive to the condensation reaction conditions or incompatible with the condensation reaction, for example a --COOH, --CH₂ OH or amino group. The protecting groups are then removed at the end of the process. Any conventional protecting group suitable for the group R₁ to R₁₀ in question may be employed, and may be introduced and subsequently removed by well-known standard methods.

The condensation reaction between compounds (I) and (II) or (I') and (III) is suitably performed in the presence of a base which is potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, caesium carbonate, sodium acetate, potassium fluoride on alumina, or triethylamine in a solvent such as dimethylformamide, or in the presence of potassium t-butoxide in t-butanol or a mixture of t-butanol and dimethylformamide. The reaction is typically performed at a temperature from 0° C. to the reflux temperature of the solvent.

The compounds of formula (I) may be prepared by a process comprising reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (III) as defined above, in the presence of a base in an organic solvent. Similarly, the compounds of formula (I') may be prepared by a process which comprises reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (II) as defined above, in the presence of a base in an organic solvent.

If necessary, the resulting compound of formula (I) or (I') can be separated from other reaction products by chromatography.

The reaction of 1,4-diacetyl-2,5-piperazinedione with the compound of formula (III) or (II) is suitably performed under the same conditions as described above for the condensation between compounds (I) and (II), or (I') and (III).

The substituted benzaldehydes of formulae (II) and (III) are known compounds or can be prepared from readily available starting materials by conventional methods. The 1,4-diacetyl-2,5-piperazinedione used as a starting material in the preparation of compounds of formula (I) may be prepared by treating 2,5-piperazinedione (glycine anhydride) with an acetylating agent. The acetylation may be performed using any conventional acetylating agent, for example acetic anhydride under reflux or, alternatively, acetic anhydride at a temperature below reflux in the presence of 4-dimethylaminopyridine.

Compounds of formula (I) may also be prepared by the microwave irradiation of a mixture comprising 1,4-diacetyl-2,5-piperazinedione, a compound of formula (III) and potassium fluoride on alumina (as base) in the absence of solvent.

Compounds of formula (I) may alternatively be prepared directly from 2,5-piperazinedione (glycine anhydride) by a process which comprises treating the 2,5-piperazinedione with a mixture comprising a compound of formula (III), sodium acetate and acetic anhydride at an elevated temperature, for example under reflux.

Compounds of formula (I') may be prepared by analogous processes, replacing compound (III) in each case by a compound of formula (II).

Compounds of formula A may also be prepared by a process comprising the microwave irradiation of (i) a mixture comprising a compound of formula (I) as defined above, a compound of formula (II) and potassium fluoride on alumina, or (ii) a mixture comprising a compound of formula (I') a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising 1,4-diacetyl-2,5-piperazinedione, a compound of formula (II), a compound of formula (III) and potassium fluoride on alumina. The irradiation is performed in the absence of a solvent.

Compounds of formula (A) may also be obtained directly by a process which comprises condensing together 1,4-diacetyl-2,5-piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of a base in an organic solvent. Suitable bases, solvents and reaction conditions are as described above for the condensation reaction between, for example, compounds (I) and (II).

An alternative direct process for the preparation of compounds of formula (A) comprises condensing together 2,5-piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of sodium acetate and acetic anhydride at elevated temperature, for example under reflux.

An alternative process for the preparation of compounds of formula (I) comprises treating a compound of formula (V): ##STR8## wherein R₆ to R₁₀ are as defined above, X is a halogen and R' is a C₁ -C₆ alkyl group, with ammonia followed by acetic anhydride.

Compounds of formula (I') may be prepared by an analogous process which comprises treating a compound of formula (V'): ##STR9## wherein R₁ to R₅, X and R¹ are as defined above, with ammonia followed by acetic anhydride.

X in formula (V) or (V') is typically iodine. R¹ is, for example, a C₁ -C₄ alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl, sec-butyl or tert-butyl group.

A review of synthetic approaches to unsaturated 3-monosubstituted and 3,6-disubstituted-2,5-piperazinediones is provided in Heterocycles, 1983, 20, 1407 (C. Shin).

Compounds of formula (A) may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods. Suitable salts include salts with pharmaceutically acceptable, inorganic or organic, bases. Examples of inorganic bases include ammonia and carbonates, hydroxides and hydrogen carbonates of group I and group II metals such as sodium, potassium, magnesium and calcium. Examples of organic bases include aliphatic and aromatic amines such as methylamine, triethylamine, benzylamine, dibenzylamine or α- or β-phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and morpholine.

Compounds of formula (A) may also be converted into pharmaceutically acceptable esters. Suitable esters include branched or unbranched, saturated or unsaturated C₁ -C₆ alkyl esters, for example methyl, ethyl and vinyl esters.

Preferred compounds of formula A are depicted by means of their substitution patterns in Table 1 which follows. The compound numbering is adhered to in the rest of the specification. Characterising data for the compounds are set out in Table 2 in Example 16.

                                      TABLE 1                                      __________________________________________________________________________      ##STR10##                                                                     COMPOUND                                         PREPARED                      NO.    R.sub.1                                                                            R.sub.2                                                                             R.sub.3     R.sub.4                                                                          R.sub.5                                                                          R.sub.6                                                                          R.sub.7                                                                           R.sub.8                                                                               R.sub.9                                                                          R.sub.10                                                                          IN EXAMPLE                    __________________________________________________________________________      21    Cl  H    H           H Cl                                                                               H H  H      H H   5                             22    H   H    H           H H H H  H      H H  10                             23    H   H    OAc         H H H H  H      H H   6                             24    H   NO.sub.2                                                                            H           H H H H  H      H H   6                             25    H   H    OEt         H H H H  H      H H   5                             26    H   H    NHAc        H H H H  OMe    H H   7                             27    H                                                                       Benzene -                   H H H H  OMe    H H  14                             28    NO.sub.2                                                                           H    H           H H H H  OMe    H H   8                             29    Cl  H    H           H Cl                                                                               H H  OMe    H H   7                             30    H   H    NH.sub.2    H H H H  H      H H  13                             31    H   OAc  H           H H H H  H      H H   6                             32    OAc H    H           H H H H  H      H H   6                             33    H   OH   H           H H H H  H      H H  13                             34    H   H    NHAc        H H H H  H      H H   5                             35    H   NO.sub.2                                                                            H           H H H NO.sub.2                                                                          H      H H  11                             36    H   H    OH          H H H H  OMe    H H  13                             37    H   H    OAc         H H H H  OMe    H H   7                             38    NHAc                                                                               H    H           H H H H  H      H H   5                             39    NH.sub.2                                                                           H    H           H H H H  H      H H  13                             40    H   H    NHAc        H H Cl                                                                               H  H      H Cl  9                             41    H   H    NMeAc       H H H H  OMe    H H   7                             42    H   H    Cl          H H H H  NHAc   H H   9                             43    H   H    CH.sub.2 OAc                                                                               H H H H  H      H H   5                             44    H   H    CH.sub.2 NHAc                                                                              H H H H  H      H H   5                             45    H   H    H           H H H H  H      H H   5                             46    H   H    SO.sub.2 Me H H H H  OMe    H H   7                             47    H   H    OBu.sup.n   H H H H  OMe    H H   7                             48    H   H    OBu.sup.n   H H H H  H      H H   5                             49    H   H    OPr.sup.i   H H H H  OMe    H H   7                             50    H   H    Bu.sup.t    H H H H  OMe    H H   7                             51    H   H    Bu.sup.t    H H H H  H      H H   5                             52    H   H    OPr.sup.i   H H H H  H      H H   5                             53    Br  H    H           H H H H  OMe    H H   7                             54    F   H    F           H H H H  H      H H   5                             55    Br  H    H           H H H H  H      H H   5                             56    H   H    CH.sub.2 NHBOC                                                                             H H H H  OMe    H H   7                             57    H   H    OMe         H H H H  CH.sub.2 SMe                                                                          H H   7                             58    H   H    NHAc        H H H H  CH.sub.2 OAc                                                                          H H   9                             59    H   H    H           H H H H  CH.sub.2 SMe                                                                          H H   5                             60    H   H    OMe         H H H H  CH.sub.2 SO.sub.2 Me                                                                  H H   7                             61    H   CH.sub.2 SAc                                                                        H           H H H H  H      H H   5                             62    H   CO.sub.2 Me                                                                         H           H H H H  H      H H   5                             63    H   CH.sub.2 SAc                                                                        H           H H H H  OMe    H H   7                             64    H   CH.sub.2 SH                                                                         H           H H H H  H      H H  13                             65    NO.sub.2                                                                           H    H           H H H H  H      H H   6                             66    H   H    CH.sub.2 NHBOC                                                                             H H H H  H      H H   5                             67    H   H    CH.sub.2 NH.sub.2                                                                          H H H H  OMe    H H  13                             68    H   H    CH.sub.2 NHBOC                                                                             H H H H  NHAc   H H   9                             69    F   H    F           H H H H  OMe    H H   7                             70    CF.sub.3                                                                           H    H           H H H H  OMe    H H   7                             71    F   H    H           H H H H  NHAc   H H   9                             72    H   H    F           H H H H  NHAc   H H   9                             73    OMe H    OMe         H H H H  OMe    H H   7                             74    H   H    NO.sub.2    H H H H  H      H H   6                             75    H   H    H           H H H H  O(CH.sub.2).sub.3 NMe.sub.2                                                           H H   5                             76    H   H    H           H H H H  CH.sub.2 SAc                                                                          H H   5                             77    F   H    F           H H H H  NHAc   H H   9                             78    CF.sub.3                                                                           H    H           H H H H  NHAc   H H   9                             79    Br  H    H           H H H H  NHAc   H H   9                             80    H   H    OMe         H H H H  CONH.sub.2                                                                            H H   7                             81    H   H    OMe         H H H H  OCOBu.sup.t                                                                           H H   7                             82    H   H    NHAc        H H H H  OCOBu.sup.t                                                                           H H   9                             83    H   H    NHCOOMe     H H H H  OMe    H H   7                             84    Cl  H    OH          H H H H  OMe    H H   7                             85    Cl  H    OH          H H H H  H      H H   5                             86    H   H    NHAc        H H H H  NMe.sub.2                                                                             H H  12                             87    H   H    NHCOCH.sub.2 OAc                                                                           H H H H  OMe    H H   7                             88    H   H    NHCOCH.sub.2 OH                                                                            H H H H  OMe    H H  13                             89    H   H    H           H H                                                Benzene-                             NMe.sub.2                                                                             H H   5                             90    H   OMe  OMe         H H H H  H      H H   5                             91    H   OMe  OMe         H H H H  OMe    H H   7                             92    H   OMe  OMe         H H H H  NHAc   H H   9                             93    H   H    OCH.sub.2 CO.sub.2 Me                                                                      H H H H  H      H H   5                             94    H   H    CH.sub.2 NHCO(CH.sub.2).sub.3 CO.sub.2 Me                                                  H H H H  H      H H   5                             95    H   H    CH.sub.2 NHCO(CH.sub.2).sub.4 CO.sub.2 Et                                                  H H H H  H      H H   5                             96    H   H    O(CH.sub.2).sub.4 CO.sub.2 Me                                                              H H H H  H      H H   5                             97    H   H    O(CH.sub.2).sub.4 CO.sub.2 H                                                               H H H H  H      H H  13                             98    H   H    O(CH.sub.2).sub.3 NMe.sub.2.HCl                                                            H H H H  H      H H  15                             99    H   H    O(CH.sub.2).sub.2 NMe.sub.2.HCl                                                            H H H H  H      H H  15                            100    H   H    CH.sub.2 NHCO(CH.sub.2).sub.3 CO.sub.2 Me                                                  H H H H  OMe    H H   7                            101    H   H    OCH.sub.2 CO.sub.2 H                                                                       H H H H  H      H H  13                            102    H   H    O(CH.sub.2).sub.2 NMe.sub.2                                                                H H H H  H      H H   5                            103    F   H    H           H H H H  OMe    H H   7                            104    H   H    CH.sub.2 OH H H H H  NHAc   H H  13                            105    H   H    H           H H H H  CN     H H   6                            __________________________________________________________________________

The diketopiperazines of formula (A), both novel and known and their pharmaceutically acceptable salts and esters (referred to hereinafter as the "present compounds") have utility as inhibitors of PAI. Elevated levels of PAI-1, by reducing the net endogenous fibrinolytic capacity, can contribute to the pathogenesis of various thrombotic disorders including myocardial infarction, deep vein thrombosis and disseminated intravascular coagulation. The present compounds therefore can act as inhibitors of the tPA/PAI-1 interaction. The present compounds can be used in the treatment of haemostatic disorders. A human or animal, e.g. a mammal, can therefore be treated by a method comprising administration of a therapeutically effective amount of a diketopiperazine of formula (A) or a pharmaceutically or veterinarily acceptable salt thereof.

Tissue plasminogen activator (tPA) is used as a fibrinolytic agent in the treatment of thrombotic disorders. The efficacy of the tPA in this role may be enhanced if it is administered together with a PAI inhibitor. A human or animal, e.g. a mammal, can therefore be treated by a method comprising the combined administration of a therapeutically effective amount of tPA and a therapeutically effective amount of any one of the present compounds. The present invention also provides products containing a diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof and tPA as a combined preparation for simultaneous, separate or sequential use in the treatment of thrombotic disorders, for example where there is inappropriate PAI activity. In such products the present compound is formulated for oral or parenteral (intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration.

As one example, during acute myocardial infarction (MI) one of the present compounds may be administered to a patient together with tPA to enhance the efficacy of the tPA treatment. As a further example, early re-occlusion following treatment of a patient with tPA may be prevented by the post-MI administration of one of the present compounds.

The compounds of formula (A) have been tested in a PAI functional assay. In this assay, a compound is incubated with PAI-1 prior to addition to the tPA assay system. Inhibition of PAI-1 results in the production of plasmin from plasminogen. In turn, plasmin cleaves the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (p-nitroaniline) which is detected spectrophotometrically at 405 nm (K. Nilsson et al, Fibrinolysis (1987) 1, 163-168). The results of the assay are reported in Example 1 which follows.

The present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The present compounds may therefore be given by injection or infusion.

The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 to 10 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration.

When one of the present compounds is administered in combination with tPA to adult humans, the dosage adopted for each route of administration is typically from 0.001 to 10 mg, more typically 0.01 to 5 mg per kg body weight for a compound of the invention and from 5 to 500 mg administered intravenously for the tPA. A suitable dosage regimen for the tPA is 100 mg given intravenously over 3 hours as follows: 10% of the total dose as an i.v. bolus over 1-2 minutes, 50% of the total dose as an infusion over 1 hour, 40% of the total dose as an infusion over the subsequent 2 hours.

A diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form. An agent for use as an inhibitor of PAI comprising any one of the present compounds is therefore provided.

For example, the solid oral forms may contain, together with the active compound, diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulphates. Such preparations may be manufactured in known manners, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular, a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. Some of the present compounds are insoluble in water. A compound may be encapsulated within liposomes.

The following Examples illustrate the invention:

EXAMPLE 1 TESTING OF THE PRESENT COMPOUNDS AS PAI INHIBITORS

Compounds of formula (A) were tested in a PAI chromogenic substrate assay. In the first assay (K. Nilsson, Fibrinolysis (1987) 1, 163-168) each compound was incubated with PAI-1 prior to addition to the tPA assay system. Inhibition of PAI-1 by the compound of formula (Aa) resulted in the production of plasmin from plasminogen. In turn, the plasmin cleaved the chromogenic substrate S2251 (Kabi-Vitrum) producing pNA (p-nitroaniline) which was detected spectrophotometrically at 405 nm.

The degrees of inhibition observed in the chromogenic substrate assay at various concentrations of compounds of formula (A) are presented in Table 3.

                  TABLE 3                                                          ______________________________________                                         INHIBITION OF PAI-1 IN THE FIRST S2251                                         CHROMOGENIC SUBSTRATE ASSAY                                                    ______________________________________                                                  Concentration in μm                                                Compound No.                                                                              100      50     25     12.5 6.25                                    ______________________________________                                         21         79       35     2      0    0                                       22         61       2      1      0    0                                       25         52       25     1      0    0                                       27         70       35     8      9                                            28         71       74     45     1    0                                       29         80       76     34     1    0                                       30         66       23     5      2                                            31         58       12     2      1    0                                       32         87       36     3      1    0                                       33         56       3      1      1    0                                       35         52       28     2                                                   36         71       6      1                                                   37         69       19     2                                                   38         64       3      1      1    1                                       39         67       20     1      1    0                                       40         61       61     23     4    1                                       41         51       45     32     8    3                                       43         59       45     3      1    1                                       44         51       2      1      1    1                                       45         53       13     1      1                                            46         39       42     38     14                                           47         75       58     14     14                                           48         73       57     26     3                                            49         60       47     8      1                                            50         62       37     22     2                                            51         79       61     38     5                                            52         68       45     15     2                                            53         55       32     9      2                                            54         50       0      1      0                                            55         65       43     11     1                                            56         82       60     15     2                                            57         82       72     38     2                                            58         60       31     1      1                                            59         71       76     60     19                                           60         62       52     25     1                                            61         83       88     69     26                                           62         83       33     13     36                                           63         69       70     44     36                                           66         85       70     46     2                                            67         53       60     46     2                                            68         63       89     67     37                                           69         68       40     14     3                                            70         94       78     21     4                                            73         50       3      1      2                                            75         59       52     33     6    2                                       76         66       75     50     5    2                                       77         33       66     80     61   1                                       78         30       57     36     4    2                                       79         42       55     27     2    1                                       80         53       9      1      0                                            81         64       1      1      0                                            82         80       3      1      1                                            83         56       1      1      1                                            84         52       38     10     2    1                                       85         35       49     43     27   13                                      86         23       37     48     41   31                                      87         78       81     70     28   0                                       88         41       49     60     40   0                                       89         63       55     66     40   7                                       90         75       85     33     6    0                                       91         50       72     3      0    0                                       92         86       44     38     12   17                                      93         91       68     39     7    2                                       94         31       62     83     76   43                                      95         69       71     45     16   10                                      96         77       75     47     29   5                                       97         0        24     73     0    0                                       98         72       71     74     67   4                                       ______________________________________                                                  Concentration in μm                                                Compound No.                                                                              60       30     15     7.5  3.75                                    ______________________________________                                         23         65       17     0      0                                            24         56       29     0      0    0                                       26         57       71     73     42                                           34         72       77     76     24                                           42         58       57     59     4    1                                       64         100      87     63     17                                           71         52       64     51     1    1                                       72         76       75     18     1    2                                       ______________________________________                                                  Concentration in μm                                                Compound No.                                                                              40       20     10     5    2.5                                     ______________________________________                                         99         68       48     17     0    0                                       ______________________________________                                                  Concentration in μm                                                Compound No.                                                                              100      50     25     12   6                                       ______________________________________                                         3          86       74     53     40   14                                      ______________________________________                                    

EXAMPLE 2 PHARMACEUTICAL COMPOSITION

Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows:

Composition for 10,000 tablets

compound of the invention (250 g)

lactose (800 g)

corn starch (415 g)

talc powder (30 g)

magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.

EXAMPLE 3 PREPARATION OF (3Z,6Z)-3-BENZYLIDENE-6-(4-METHOXYBENZYLIDENE)-2,5-PIPERAZINEDIONE (3) (SCHEME1) ##STR11## 1,4-Diacetyl-2,5-piperazinedione (8)

1,4-Diacetyl-2,5-piperazine-2,5-dione (8) was prepared by the published procedure (S. M. Marcuccio and J. A. Elix, Aust. J. Chem., 1984, 37, 1791).

(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9)

(3Z )-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) was prepared by the published procedure (T. Yokoi, L.-M. Yang, T. Yokoi, R.-Y. Wu, and K.-H. Lee, J. Antibiot, 1988, 41, 494).

(3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-2,5-piperazinedione (3)

A mixture of (3Z)-1-acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) (1.0 g, 3.6 mmol), benzaldehyde (430 μl, 4.2 mmol) and triethylamine (1.14 ml), 8.2 mmol), in dry DMF (20 ml), was heated at 130° C. for 18 h. The reaction mixture was cooled to room temperature and poured into ethyl acetate (100 ml). A yellow solid precipitated which was filtered off and dried. Yield 360 mg (31%). C₁₉ H₁₆ N₂ O₃

¹ H nmr (400 MHz d₆ -DMSO): δ: 3.80 (3H, s, o-Me); 6.77 (1H, s, CH═C); 6.78 (1H, s, CH═C); 6.98 (2H, d, J=8 Hz, 2×C--H on Ar--OMe); 7.30-7.56 (7H, m, Ph and 2×C--H on Ar--OMe); 10.15 (2H, br.s, N--H).

¹³ C nmr (100 MHz d₆ -DMSO) δ: 58.68; 117.66; 118.03; 118.77; 128.11; 128.92; 129.95; 131.53; 132.11; 132.69; 134.44; 136.59; 161.39; 161.62; 162.71.

ms (desorption chemical ionisation, ammonia):

m/z (% relative intensity): 321 (100) MH⁺.

ir: KBr (diffuse reflectance):

v max (cm⁻¹): 1620, 1700, 3100, 3220.

Elemental analysis: Calculated for C₁₉ H₁₆ N₂ O₃ : C 71.24, H 5.03, N 8.74. Found: C 70.92, H 5.02, N 8.80. C 70.89, H 5.06, N 8.79%

EXAMPLE 4 PREPARATION OF (3Z,6Z)-3-BENZYLIDENE-6-(4-METHOXYBENZYLIDENE)-1-METHYL-2,5-PIPERAZINEDIONE (1) (SCHEME 2) ##STR12##

Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield 1-acetyl-3-benzylidenepiperazine-2,5-dione (18).

Compound 18 is then condensed, in the presence of caesium carbonate or triethylamine in DMF, with 4-methoxybenzaldehyde to yield compound 3.

Reference Example 1 Preparation of 1-acetyl-3-benzylidene-2,5-piperazinedione

1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound (8) mentioned in Example 3, was heated at 120°-130° C. in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off. The filtrate was dried (MgSO₄) and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38%) of the title compound as a yellow solid.

¹ H NMR (CDCl₃ 400 MHz) δ=2.69 (3H, s) 4.54 (2H, s) 7.20 (1H, s) 7.40 (3H, m), 7.48 (2H, m), 7.93 (1H, br.s)

MS(DCI,NH₃): 262 (MNH₄ ⁺, 20%), 245 (MH⁺, 53%), 220 (52%), 204 (100%), 203 (100%)

    ______________________________________                                         Microanalysis                                                                              C            H      N                                              ______________________________________                                         Calc        63.93        4.95   11.47                                          Found       64.11        5.02   11.41                                                      64.05        4.90   11.44                                          ______________________________________                                    

EXAMPLE 5 Preparation of compound 96

1-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), prepared according to Reference Example 1, was treated with 5-(4-formylphenoxy)pentanoic acid, methyl ester in the presence of Cs₂ CO₃ (1-1.1 equivalents) in DMF at 80°-100° C. for 1-8 hours. The title compound was obtained in 39% yield.

By the same method, but replacing 5-(4-formylphenoxy)pentanoic acid, methyl ester (which is benzaldehyde substituted at position 4 by --O(CH₂)₄ CO₂ Me) by the appropriately substituted benzaldehyde, the following compounds were prepared:

    ______________________________________                                         Compound  Yield (%)   Compound  Yield (%)                                      ______________________________________                                         21        66          25        37                                             34        56          43        54                                             38        84          45        91                                             44        44          51        68                                             48        69          54        69                                             52        72          59        50                                             55        73          62        63                                             61        44          75        49                                             66        15          85        15                                             76        60          89        37                                             90        74          93        69                                             94        39          95        26                                             96        39          102       45                                             ______________________________________                                    

Characterising data for the compounds are set out in Example 16.

EXAMPLE 6 Preparation of Compound 31

1-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), prepared according to Reference Example 1, was treated with 3-acetoxybenzaldehyde (one equivalent) in the presence of triethylamine (1-2 equivalents) in DMF at 130° C. for 2-6 hours. The title compound was obtained in 61% yield.

By the same method, but replacing 3-acetoxybenzaldehyde by the appropriately substituted benzaldehyde, the following compounds were prepared:

    ______________________________________                                                Compound                                                                               Yield (%)                                                       ______________________________________                                                23      16                                                                     24      43                                                                     32      41                                                                     65      27                                                                     74      77                                                                     105     50                                                              ______________________________________                                    

Characterising data are provided in Example 16.

EXAMPLE 7 Preparation of compound 103

1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent), which is compound (9) mentioned in Example 3, was treated with 2-fluorobenzaldehyde (1 equivalent) in the presence of Cs₂ CO₃ (1-1.1 equivalents) in DMF at 80°-100° C. for 1-6 hours. The title compound was obtained in 69% yield.

By the same method, but replacing the 2-fluorobenzaldehyde by the appropriately substituted benzaldehyde with the exception of compound 84 which was prepared by condensation with 4-acetoxy-2-chlorobenzaldehyde, the following compounds were prepared:

    ______________________________________                                         Compound  Yield (%)   Compound  Yield (%)                                      ______________________________________                                         26        80          63        71                                             29        70          69        20                                             37        21          70        10                                             41        34          73        38                                             46        16          80        45                                             47        46          81         5                                             49        60          83        41                                             50        56          84        Low                                            53        77          87        33                                             57        49          91        74                                             60        71          100       20                                                                   103       69                                             ______________________________________                                    

Characterising data are provided in Example 16.

EXAMPLE 8 Preparation of compound 28

1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent), compound (9) in Example 3, was treated with 2-nitrobenzaldehyde (1 equivalent) in triethylamine (1-2 equivalents) and DMF at 130° C. for 2-6 hours. The title compound was obtained in 45% yield. Characterising data are set out in Example 16.

Reference Example 2 Preparation of 1-acetyl-3-(4-acetamidobenzylidene)-2,5-piperazinedione

1,4-Diacetyl-2,5-piperazinedione (10.0 g, 50 mmol), prepared by the published procedure mentioned in Example 3, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120° C. After 21/2 h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.

¹ H NMR (CDCl₃ +TFA, 400 MHz) δ=2.32 (3H, s) 2.72 (3H, s) 4.68 (2H, s) 7.36 (1H, s) 7.45 (2H, d, J=8 Hz) 7.60 (2H, d, J=8 Hz)

    ______________________________________                                         Microanalysis                                                                              C            H      N                                              ______________________________________                                         Calc        59.80        5.02   13.95                                          Found       60.08        5.09   13.89                                                      60.11        5.07   13.86                                          ______________________________________                                    

EXAMPLE 9 Preparation of Compound 77

1-Acetyl-3-(4-acetamidobenzylidene)-2,5-piperazinedione (1 equivalent), prepared according to Reference Example 2, was treated with 2,4-difluorobenzaldehyde (1 equivalent) in the presence of Cs₂ CO₃ (1-1.1 equivalents) in DMF at 80°-100° C. for 1-6 hours. The title compound was obtained in 60% yield.

By the same method, but replacing 2,4-difluorobenzaldehyde by the appropriately substituted benzaldehyde, the following compounds were obtained:

    ______________________________________                                         Compound  Yield (%)   Compound  Yield (%)                                      ______________________________________                                         42        50          40        40                                             68        26          58        22                                             72        41          71        36                                             79        11          78        16                                             92        68          82        16                                             ______________________________________                                    

Characterising data are set out in Example 16.

EXAMPLE 10 Preparation of compound 22

1,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with benzaldehyde (2.1 equivalents) in the presence of triethylamine (2.5 equivalents) in DMF at 130° C. for 8 hours. The title compound was obtained in 89% yield. Characterising data are set out in Example 16.

EXAMPLE 11 Preparation of compound 35

1,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with 3-nitrobenzaldehyde (1 equivalent) in the presence of triethylamine (1 equivalent) in DMF at room temperature for 18-20 hrs. The title compound was obtained in 9% yield together with 1-acetyl-3-(3-nitrobenzylidene)-2,5-piperazinedione (66% yield). Characterising data are set out in Example 16.

Reference Example 3 Preparation of 1-acetyl-3-(4-N,N-dimethylaminobenzylidine)-2,5-piperazinedione

1,4-Diacetyl-2,5-piperazinedione, (1 equivalent), prepared as described in Example 3, was treated with 4-N,N-dimethylaminobenzaldehyde (1 equivalent) in the presence of Et₃ N in DMF at 130° C. for 24 hrs. The title compound was obtained in 18% yield

EXAMPLE 12 Preparation of Compound 86

1-Acetyl-3-(4-dimethylaminobenzylidene)-2,5-piperazinedione (1 equivalent) as described in Reference Example 3 was treated with 4-acetamidobenzaldehyde (1 equivalent) in the presence of Cs₂ CO₃ (1 equivalent) in DMF at 80° C. for 2-6 hours. The title compound was obtained in 56% yield. Characterising data are set out in Example 16.

EXAMPLE 13 Interconversions of compounds of formula A

(i) Compound 31, prepared as described in Example 6, was treated with aqueous lithium hydroxide in a mixture of MeOH and THF at room temperature for 2-3 hrs to give compound 33 in 91% yield.

(ii) Compound 61, prepared as described in Example 5, was treated with aqueous lithium hydroxide in a mixture of MeOH and THF at room temperature for 3 hours to give compound 64 in 57% yield.

(iii) Compound 96, prepared as described in Example 5, was treated with aqueous sodium hydroxide in THF at room temperature for 4 hours to give compound 97 in 54% yield.

(iv) Compound 37, prepared as described in Example 7, was treated with aqueous sodium hydroxide in THF at room temperature for 8 hrs to give compound 36 in 30% yield.

(v) Compound 56, prepared as described in Example 7, was treated with trifluoroacetic acid in CH₂ Cl₂ at room temperature for 12 hrs to give compound 67 in 96% yield.

(vi) Compound 87, prepared as described in Example 7, was treated with aqueous sodium hydroxide in THF at room temperature for 4 hours to give compound 88 in 69% yield.

(vii) Compound 65, prepared as described in Example 6 was hydrogenated over 10% palladium on carbon as catalyst in CH₂ Cl₂ in the presence of a few drops of trifluoroacetic acid to give compound 39 in 38% yield. Under the same conditions of hydrogenation compound 74 was converted into compound 30 in 95% yield.

(viii) Compound 93, prepared as described in Example 5, was hydrolysed by treatment with aqueous sodium hydroxide in a mixture of MeOH and THF at room temperature for 18 hours to give compound 101 in 72% yield.

(ix) Compound 58, prepared as described in Example 9, was hydrolysed by treatment with aqueous sodium hydroxide in THF at room temperature for 3 hours to give compound 104 in 90% yield.

Characterising data for all compounds prepared in this Example are provided in Example 16.

EXAMPLE 14 Preparation of Compound 27

1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent), compound (9) in Example 3, was treated with 2-naphthaldehyde (1 equivalent) in the presence of Cs₂ CO₃ (1.0-1.1 equivalents) in DMF at 80°-100° C. for 1-6 hours. The title compound was obtained in 84% yield.

Characterising data are provided in Example 16.

EXAMPLE 15 Preparation of Salts

Compound 98, the hydrochloride salt of compound 102, was prepared by treatment of a solution of compound 102 in THF with 2 molar hydrochloric acid followed by sonication until a clear solution was obtained. The solvent was then removed in vacuo and the residual solution was freeze-dried to give compound 98.

Compound 99 was prepared by bubbling HCl gas through a solution of the corresponding free base in THF, followed by evaporation to dryness.

Characterising data are provided in Example 16.

EXAMPLE 16 Characterization of compounds of formula A

The compounds prepared in the preceding Examples, were characterised by mass spectroscopic, microanalytical, proton nuclear magnetic resonance and, in some cases, infra-red techniques. The results are set out in Table 2:

                                      TABLE 2                                      __________________________________________________________________________                Mass spec                                                                               .sup.1 H nmr                                                          m/z, mass,                                                                              Solvent                                                    Mol. Formula                                                                              intensity                                                                               δ  Microanalysis                                                                             Infra-red                              N.sup.o                                                                           (M. Wt) (mode)   all 400 MHz                                                                             Calc Found cm.sup.-1                              __________________________________________________________________________     21 C.sub.18 H.sub.12 N.sub.2 O.sub.2 Cl.sub.2                                             359, MH.sup.+, 100%;                                                                    d.sub.6 -DMSO                                                                           C 60.19                                                                             59.33                                                                             59.37                                                                             3200,                                             376, MNH.sub.4.sup.+,                                                                   7.6-7.30(m, 8H),                                                                        H 3.37                                                                              3.44                                                                              3.68                                                                              3050,                                             15%; 363, 10%;                                                                          6.81(s, 1H),                                                                            N 7.80                                                                              7.55                                                                              7.48                                                                              1680,                                             362, 10%; 361,                                                                          6.60(s, 1H)                                                                             Cl                                                                               19.74                                                                             19.22                                                                             19.40                                                                             1620,                                             60%; 323, 40%                1400, 1370                                        (DCI, NH.sub.3)                                                     22 C.sub.18 H.sub.14 O.sub.2 H.sub.2                                                      291, MH.sup.+                                                                           d.sub.6 -DMSO                                                                           C 74.47                                                                             74.39                                                                             74.20                                        (290)   (DCI, NH.sub.3)                                                                         6.54(1H, s),                                                                            H 4.86                                                                              4.78                                                                              4.75                                                          6.71(1H, s),                                                                            N 9.65                                                                              9.68                                                                              9.60                                         mixture of       6.80(2H, s),                                                  isomers          7.20-7.60(20H,                                                                 m),                                                                            10.17(2H, broad                                                                singlet),                                                                      10.80(0.5H, broad                                                              singlet)                                                   23 C.sub.20 H.sub.16 N.sub.2 O.sub.4                                                      348(M.sup.+, 23%);                                                                      CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 68.96                                                                             69.05                                                                             69.08                                                                             1620,                                             306, 100%                                                                               2.40(3H, s), 7.25                                                                       H 4.63                                                                              4.56                                                                              4.57                                                                              1690,                                             (EI)     (2H, d, J=7Hz),                                                                         N 8.04                                                                              8.15                                                                              8.15                                                                              1760, 3200                                                 7.29(1H, s),                                                                   7.40-7.51(8H, m)                                           24 C.sub.18 H.sub.13 N.sub.3 O.sub.4                                                      336, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 64.48                                                                             65.06                                                                             65.03                                        (335)   353, MNH.sub.4.sup.+,                                                                   8.30-8.26(m, 2H),                                                                       H 3.91                                                                              3.93                                                                              3.98                                                 10%; 306, 20%;                                                                          7.76-7.67(m, 2H),                                                                       N 12.53                                                                             12.19                                                                             12.20                                                291, 70% 7.53-7.43(m, 5H),                                                     (DCI/NH.sub.3)                                                                          7.32(s, 1H),                                                                   7.26(s, 1H)                                                25 C.sub.20 H.sub.18 N.sub.2 O.sub.3                                                      335, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 71.84                                                                             71.83                                                                             71.95                                        (334)   305, 10%; 291,                                                                          7.49-7.39(m, 7H),                                                                       H 5.43                                                                              5.35                                                                              5.36                                                 20%; 277, 10%;                                                                          7.20(d, 2H),                                                                            N 8.38                                                                              8.38                                                                              8.41                                                 161, 20% 7.00(d, 2H),                                                          (DCI/NH.sub.3)                                                                          4.11(q, 2H),                                                                   1.45(t, 3H)                                                26 C.sub.21 H.sub.19 N.sub.3 O.sub.4                                                      279, 10%; 378                                                                           CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.83                                                                             66.77                                                                             66.94                                        (377)   MH.sup.+ ; 395, MNH.sub.4.sup.+,                                                        7.60(1.62H, d),                                                                         H 5.07                                                                              5.04                                                                              4.96                                                 50%      7.55(0.38H, d),                                                                         N 11.13                                                                             11.07                                                                             11.10                                                (DCI/NH.sub.3)                                                                          7.50(3.55H, m),                                                                7.45(0.45H, d),                                                                7.28(1H, s),                                                                   7.22(1H, s),                                                                   7.05(2H, d),                                                                   3.90(3H, s),                                                                   2.38(2.5H, s),                                                                 2.25(0.5H, s)                                              27 C.sub.23 H.sub.18 N.sub.2 O.sub.2                                                      371, MH.sup.+ ; 388,                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 74.58                                                                             74.48                                                                             74.39                                                MNH.sub.4.sup.+, 2%                                                                     8.02(1H, s),                                                                            H 4.90                                                                              4.86                                                                              4.93                                                 (DCI/NH.sub.3)                                                                          7.95(2H, m),                                                                            N 7.56                                                                              7.55                                                                              7.58                                                          7.90(1H, m),                                                                   7.58(2H, m),                                                                   7.50(1H, dd),                                                                  7.48(2H, d),                                                                   7.40(1H, s),                                                                   7.25(1H, s),                                                                   7.05(2H, d),                                                                   3.90(3H, s)                                                28 C.sub.19 H.sub.15 N.sub.3 O.sub.5                                                      366, MH.sup.+ ; 383,                                                                    CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 62.46                                                                             62.55                                                                             62.45                                        (365)   MNH.sub.4.sup.+, 80%                                                                    8.30(1H, d),                                                                            H 4.13                                                                              4.17                                                                              4.16                                                 (DCI/NH.sub.3)                                                                          7.77(1H, m),                                                                            N 11.50                                                                             11.60                                                                             11.50                                                         7.67(1H, m),                                                                   7.48(4H, m),                                                                   7.25(1H, s),                                                                   7.02(2H, d),                                                                   3.90(3H, s)                                                29 C.sub.19 H.sub.14 N.sub.2 O.sub.3 Cl.sub.2                                             355, 15%; 389,                                                                          CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 58.63                                                                             58.40                                                                             58.41                                                MH.sup.+ ; 406, MNH.sub.4.sup.+,                                                        7.40(4H, m),                                                                            H 3.63                                                                              3.64                                                                              3.66                                                 2%       7.35(1H, pt),                                                                           N 7.20                                                                              7.13                                                                              7.12                                                 (DCI/NH.sub.3)                                                                          7.25(1H, s),                                                                   7.10(1H, s),                                                                   7.02(2H, d),                                                                   3.90(3H, s)                                                30 C.sub.18 H.sub.15 N.sub.3 O.sub.2                                                      306, MH.sup.+, 100%                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (305)   (DCI/NH.sub.3)                                                                          7.59(d, 2H),                                                                   7.53(d, 2H),                                                                   7.51-7.42(m, 5H),                                                              7.31(s, 1H),                                                                   7.22(s, 1H)                                                31 C.sub.20 H.sub.16 N.sub.2 O.sub.4                                                      349, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 68.96                                                                             69.14                                                                             69.16                                        (348)   366, MNH.sub.4.sup.+, 10%                                                               2.39(3H, s),                                                                            H 4.63                                                                              4.63                                                                              4.63                                                 (DCI/NH.sub.3)                                                                          7.14-7.54(11H, m)                                                                       N 8.04                                                                              8.07                                                                              8.00                                      32 C.sub.20 H.sub.16 N.sub.2 O.sub.4                                                      366, MNH.sub.4.sup.+,                                                                   CDCl.sub.3                                                                              C 68.96                                                                             68.88                                                                             69.07                                        (348)   38%; 349, MH.sup.+,                                                                     2.40(3H, s),                                                                            H 4.63                                                                              4.56                                                                              4.55                                                 100%     6.90(1H, s),                                                                            N 8.04                                                                              8.30                                                                              8.30                                                 (DCI/NH.sub.3)                                                                          7.04(1H, s),                                                                   7.20(1H, d),                                                                   7.30-7.50(8H, m),                                                              8.12(1H, bs),                                                                  8.19(1H, bs)                                               33 C.sub.18 H.sub.14 N.sub.2 O.sub.3                                                      324, MNH.sub.4.sup.+, 5%;                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (306)   307, MH.sup.+, 100%                                                                     6.97-7.50(11H, m)                                                     (DCI/NH.sub.3)                                                      34 C.sub.20 H.sub.17 N.sub.3 O.sub.3                                                      348, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 69.15                                                                             68.87                                                                             68.96                                        (347)   305, 70%; 227,                                                                          7.61(d, 2H),                                                                            H 4.93                                                                              4.73                                                                              4.86                                                 30%; 145, 80%                                                                           7.55-7.43(m, 7H),                                                                       N 12.10                                                                             11.93                                                                             11.91                                                (DCI.sup.+)                                                                             7.29(s, 1H),                                                          (DCI/NH.sub.3)                                                                          7.24(s, 1H),                                                                   2.37+2.25                                                                      (singlets, 3H,)                                                                (2.37-77%, 2.25-                                                               23%)                                                       35 C.sub.18 H.sub.12 O.sub.6 N.sub.4                                                      380, MH.sup.+, 30%;                                                                     CDCl.sub.3, CF.sub.3 CO.sub.2 D                                                         C 56.85                                                                             56.84                                                                             56.74                                        (380)   398, MNH.sub.4.sup.+,                                                                   8.37-8.34(m, 4H),                                                                       H 3.18                                                                              3.04                                                                              3.05                                                 100%     7.83-7.70(m, 4H),                                                                       N 14.73                                                                             14.69                                                                             14.67                                                (DCI/NH.sub.3)                                                                          7.40(s, 2H)                                                36 C.sub.19 H.sub.16 N.sub.2 O.sub.4                                                      337, MH.sup.+ ; 351,                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (336)   MNH.sub.4.sup.+, 5%                                                                     7.40(4H, m),                                                          (DCI/NH.sub.3)                                                                          7.22(2H, d),                                                                   7.00(2H, d),                                                                   6.98(2H, d),                                                                   3.90(3H, s)                                                37 C.sub.21 H.sub.18 N.sub.2 O.sub.5                                                      379, MH.sup.+ ; 396,                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.66                                                                             66.38                                                                             66.63                                        (378)   MNH.sub.4.sup.+, 40%                                                                    7.48(2H, d),                                                                            H 4.79                                                                              4.71                                                                              4.71                                                 (DCI/NH.sub.3)                                                                          7.44(2H, d),                                                                            N 7.40                                                                              7.35                                                                              7.41                                                          7.20(4H, m),                                                                   7.02(2H, d),                                                                   3.90(3H, s),                                                                   2.40(3H, s)                                                38 C.sub.20 H.sub.17 N.sub.3 O.sub.3                                                      348, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 69.15                                                                             68.21                                                                             68.47                                        (347)   365, MNH.sub.4.sup.+,                                                                   7.70-7.68(m, 1H),                                                                       H 4.93                                                                              4.86                                                                              4.89                                                 10%; 331, 10%;                                                                          7.52-7.38(m, 8H),                                                                       N 12.10                                                                             11.79                                                                             11.85                                                306, 10% 7.28(s, 1H),                                                          (DCI/NH.sub.3)                                                                          7.14(s, 1H),                                                                   2.30+2.08                                                                      (singlets, 3H)                                             39 C.sub.18 H.sub.15 N.sub.3 O.sub.2                                                      306, MH.sup.+, 100%                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (305)   (DCI/NH.sub.3)                                                                          7.62-7.48(m, 9H),                                                              7.28(s, 1H),                                                                   7.17(s, 1H)                                                40 C.sub.20 H.sub.15 N.sub.3 O.sub.3 Cl.sub.2                                             433/435, MNH.sub.4.sup.+,                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 57.71                                                                             57.51                                                                             57.55                                        (415)   100%; 416/418,                                                                          2.36(3H, s),                                                                            H 3.63                                                                              3.81                                                                              3.88                                                 MH.sup.+, 55%; 380,                                                                     7.14(1H, s),                                                                            N 10.09                                                                             10.34                                                                             10.13                                                13%      7.26(1H, s),                                                          (DCI/NH.sub.3)                                                                          7.34(1H, m),                                                                   7.42(2H, d),                                                                   7.49(2H, d),                                                                   7.60(2H, d)                                                41 C.sub.22 H.sub.21 N.sub.3 O.sub.4                                                      409, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 67.50                                                                             66.75                                                                             66.63                                        (391)   29%; 392, MH.sup.+,                                                                     2.02(3H, s),                                                                            H 5.41                                                                              5.34                                                                              5.36                                                 100%; 350, 32%                                                                          3.34(3H, s),                                                                            N 10.74                                                                             10.57                                                                             10.52                                                (DCI/NH.sub.3)                                                                          3.89(3H, s),                                                                   7.01(2H, d),                                                                   7.21(1H, s),                                                                   7.22(1H, s),                                                                   7.33(2H, d),                                                                   7.43(2H, d),                                                                   7.52(2H, d)                                                42 C.sub.20 H.sub.16 N.sub.3 O.sub.3 Cl                                                   399, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (381)   70%; 401, 32%;                                                                          2.35(3H, s),                                                          382, MH.sup.+, 100%;                                                                    7.21(2H, d),                                                          384, 55% 7.49(2H, d),                                                          (DCI/NH.sub.3)                                                                          7.50(4H, m),                                                                   7.61(2H, d)                                                43 C.sub.21 H.sub.18 N.sub.2 O.sub.4                                                      380, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 69.60                                                                             69.72                                                                             69.86                                        (362)   70%; 363, MH.sup.+,                                                                     2.19(3H, s),                                                                            H 5.01                                                                              4.95                                                                              4.94                                                 100%; 303, 44%;                                                                         5.2(2H, s),                                                                             N 7.73                                                                              7.79                                                                              7.79                                                 291, 13%; 279,                                                                          7.25(2H, d),                                                          11%      7.40-7.52(9H, m)                                                      (DCI/NH.sub.3)                                                      44 C.sub.21 H.sub.19 N.sub.3 O.sub.3                                                      379, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 69.79                                                                             69.32                                                                             69.19                                        (361)   10%; 362, MH.sup.+,                                                                     2.19(3H, s),                                                                            H 5.30                                                                              5.38                                                                              5.26                                                 100%; 319, 10%;                                                                         4.51(2H, s),                                                                            N 11.63                                                                             11.29                                                                             11.13                                                291, 11% 7.21(2H, s),                                                          (DCI/NH.sub.3)                                                                          7.32-7.52(9H, m)                                           45 C.sub.18 H.sub.14 N.sub.2 O.sub.2                                                               d.sub.6 -DMSO                                                                           C 74.47                                                                             73.95                                                                             73.92                                        (290)            6.78(2H, s),                                                                            H 4.86                                                                              4.80                                                                              4.81                                                          7.35(2H, t),                                                                            N 9.65                                                                              9.57                                                                              9.56                                                          7.40(4H, t),                                                                   7.56(4H, d)                                                46 C.sub.20 H.sub.18 N.sub.2 O.sub.5 S                                                    351, 30%; 399,                                                                          CDCl.sub.3                                                                              C 60.29                                                                             59.89                                                                             59.99                                        (398)   MH.sup.+ ; 416, MNH.sub.4.sup.+                                                         8.07(2H, d),                                                                            H 4.55                                                                              4.54                                                                              4.56                                                 (DCI/NH.sub.3)                                                                          7.65(2H, d),                                                                            N 7.03                                                                              6.90                                                                              6.96                                                          7.47(2H, d),                                                                   7.25(2H),                                                                      7.05(2H, d),                                                                   3.90(3H, s),                                                                   3.18(3H, s)                                                47 C.sub.23 H.sub.24 N.sub.2 O.sub.4                                                      MH.sup.+ CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 70.39                                                                             70.06                                                                             70.13                                        (392)   (DCI/NH.sub.3)                                                                          7.40(4H, m),                                                                            H 6.16                                                                              6.06                                                                              6.10                                                          7.20(2H, s),                                                                            N 7.14                                                                              7.20                                                                              7.13                                                          7.00(4H, m),                                                                   4.08(2H, t),                                                                   3.88(3H, s),                                                                   1.82(2H, m),                                                                   1.53(2H, m),                                                                   1.00(3H, t)                                                48 C.sub.22 H.sub.22 N.sub.2 O.sub.3                                                      MH.sup.+ CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 72.91                                                                             72.14                                                                             72.09                                        (362)   (DCI/NH.sub.3)                                                                          7.48(7H, m),                                                                            H 6.12                                                                              5.79                                                                              5.99                                                          7.25(2H, d),                                                                            N 7.73                                                                              7.71                                                                              7.69                                                          7.00(2H, d),                                                                   4.05(2H, t),                                                                   1.82(2H, m),                                                                   1.48(2H, m),                                                                   0.98(3H, t)                                                49 C.sub.22 H.sub.22 N.sub.2 O.sub.4                                                      MH.sup.+ CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 69.83                                                                             69.85                                                                             69.90                                        (378)   (DCI/NH.sub.3)                                                                          7.38(4H, m),                                                                            H 5.86                                                                              5.76                                                                              5.80                                                          7.18(2H, s),                                                                            N 7.40                                                                              7.41                                                                              7.42                                                          6.98(4H, pt),                                                                  4.62(1H, m),                                                                   3.88(3H, s),                                                                   1.38(6H, d)                                                50 C.sub.23 H.sub.24 N.sub.2 O.sub.3                                                      MH.sup.+ CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 73.38                                                                             73.21                                                                             73.29                                        (376)   (DCI/NH.sub.3)                                                                          7.55(2H, d),                                                                            H 6.43                                                                              6.45                                                                              6.45                                                          7.45(2H, d),                                                                            N 7.44                                                                              7.44                                                                              7.44                                                          7.40(2H, d),                                                                   7.25(2H),                                                                      7.05(2H, d),                                                                   3.90(3H, s),                                                                   1.35(9H, s)                                                51 C.sub.22 H.sub.22 N.sub.2 O.sub.2                                                      331, MH.sup.+, 10%;                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 76.28                                                                             75.57                                                                             75.53                                                347, MNH.sub.4.sup.+, 364                                                               7.48(7H, m),                                                                            H 6.40                                                                              6.28                                                                              6.34                                                 (DCI/NH.sub.3)                                                                          7.39(2H, d),                                                                            N 8.09                                                                              8.04                                                                              8.04                                                          7.25(2H),                                                                      1.35(9H, s)                                                52 C.sub.21 H.sub.20 N.sub.2 O.sub.3                                                      291, 10%; 349,                                                                          CDCl.sub.3 +CF.sub.3 CO.sub.2 D                                                         C 72.40                                                                             72.30                                                                             72.42                                                MH.sup.+ 7.45(7H, m),                                                                            H 5.79                                                                              5.76                                                                              5.65                                                 (DCI/NH.sub.3)                                                                          7.25(1H, s),                                                                            N 8.04                                                                              8.15                                                                              8.12                                                          7.23(1H, s),                                                                   7.02(2H, d),                                                                   4.55(1H, m),                                                                   1.40(6H, d)                                                53 C.sub.19 H.sub.15 N.sub.2 O.sub.3 Br                                                   399:401  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 57.16                                                                             57.08                                                                             56.95                                        (399 ± 1)                                                                           (100:100)%; 321                                                                         3.88(3H, s),                                                                            H 3.79                                                                              3.77                                                                              3.78                                                 62%      7.01(2H, d),                                                                            N 7.02                                                                              6.94                                                                              6.96                                                 (DCI/NH.sub.3)                                                                          7.19(1H, s),                                                                            Br                                                                               20.01                                                                             20.03                                                            7.22(1H, s),                                                                   7.28-7.31(1H, m),                                                              7.36-7.43(4H, m),                                                              7.70(1H, d)                                                54 C.sub.18 H.sub.12 N.sub.2 O.sub.2 F.sub.2                                              327, 100%                                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.26                                                                             66.44                                                                             66.50                                        (326)   (DCI/NH.sub.3)                                                                          6.90-7.03(2H, m),                                                                       H 3.71                                                                              3.74                                                                              3.72                                                          7.15(1H, s),                                                                            N 8.59                                                                              8.65                                                                              8.66                                                          7.31(1H, s),                                                                   7.38-7.52(6H, m)                                           55 C.sub.18 H.sub.13 N.sub.2 O.sub.2 Br                                                   369:371, CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 58.56                                                                             58.57                                                                             58.28                                        (369 ± 1)                                                                           (100:100)%;                                                                             7.29-7.33(2H, m),                                                                       H 3.55                                                                              3.45                                                                              3.46                                                 386:388, 7.39-7.53(8H, m),                                                                       N 7.59                                                                              7.62                                                                              7.47                                                 (19:19)%; 291,                                                                          7.71(1H, d)                                                                             Br                                                                               21.64                                                                             21.33                                                                             21.35                                                63%                                                                            (DCI/NH.sub.3)                                                      56 C.sub.25 H.sub.27 N.sub.3 O.sub.5                                                      467, MNH.sub.4+, 3%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.80                                                                             66.45                                                                             66.50                                        (449)   450, MH.sup.+, 7%;                                                                      1.48(9H, s),                                                                            H 6.05                                                                              5.97                                                                              5.94                                                 449, M.sup.+, 12%;                                                                      3.90(3H, s),                                                                            N 9.35                                                                              9.28                                                                              9.29                                                 394, 100%; 351,                                                                         4.34(2H, s),                                                          14%; 333, 16%                                                                           7.03(2H, d),                                                          (DCI/NH.sub.3)                                                                          7.21(1H, s),                                                                   7.33-7.47(6H, m),                                                              7.51(1H, s)                                                57 C.sub.21 H.sub.20 N.sub.2 O.sub.3 S                                                    398, MNH.sub.4.sup.+, 4%;                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.30                                                                             65.87                                                                             65.82                                        (380)   381, MH.sup.+, 100%;                                                                    2.02(3H, s),                                                                            H 5.30                                                                              5.16                                                                              5.14                                                 333, 24% 3.71(2H, s),                                                                            N 7.36                                                                              7.32                                                                              7.30                                                 (DCI/NH.sub.3)                                                                          3.39(3H, s),                                                                            S 8.43                                                                              7.45                                                                              7.62                                                          7.02(2H, d),                                                                   7.21(2H, s),                                                                   7.38-7.49(6H, m)                                           58 C.sub.23 H.sub.21 N.sub.3 O.sub.5                                                      437, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (419)   18%; 420, MH.sup.+,                                                                     2.21(3H, s),                                                          90%; 405, 30%;                                                                          2.34(3H, s),                                                          360, 100%; 317,                                                                         5.21(2H, s),                                                          8%       7.25(2H, d),                                                          (DCI/NH.sub.3)                                                                          7.41-7.50(6H, m),                                                              7.59(2H, d)                                                59 C.sub.20 H.sub.18 N.sub.2 O.sub.25                                                     368, MNH.sub.4.sup.+, 8%;                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 68.55                                                                             67.94                                                                             67.89                                        (350)   351, MH.sup.+, 100%;                                                                    2.03(3H, s),                                                                            H 5.18                                                                              5.00                                                                              4.99                                                 303, 31%; 291,                                                                          3.72(2H, s),                                                                            N 7.99                                                                              8.01                                                                              8.00                                                 8%       7.28(1H, s),                                                          (DCI/NH.sub.3)                                                                          7.38-7.51(10H, m)                                          60 C.sub.21 H.sub.20 N.sub.2 O.sub.5 S                                                    430, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 61.15                                                                             60.86                                                                             60.83                                        (412)   28%; 413, MH.sup.+,                                                                     2.96(3H, s),                                                                            H 4.89                                                                              4.83                                                                              4.83                                                 100%; 333, 35%                                                                          3.91(3H, s),                                                                            N 6.79                                                                              6.83                                                                              6.83                                                 (DCI/NH.sub.3)                                                                          4.45(2H, s),                                                                            S 7.77                                                                              7.37                                                                              7.47                                                          7.08(2H, d),                                                                   7.24(2H, d),                                                                   7.42(2H, d),                                                                   7.51(4H, m)                                                61 C.sub.21 H.sub.18 N.sub.2 O.sub.3 S                                                    379, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.65                                                                             66.28                                                                             66.20                                        (378)   337, 8%; 305,                                                                           2.39(3H, s),                                                                            H 4.79                                                                              4.71                                                                              4.74                                                 8%       4.15(2H, s),                                                                            N 7.40                                                                              7.58                                                                              7.61                                                 (DCI/NH.sub.3)                                                                          7.15-7.50(11H, m)                                          62 C.sub.20 H.sub.16 N.sub.2 O.sub.4                                                      366, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (348)   40%; 349, M.sup.+ H,                                                                    4.00(3H, s),                                                          100%     7.25-7.69(9H, m),                                                     (DCI/NH.sub.3)                                                                          8.09-8.14(2H, m),                                          63 C.sub.22 H.sub.20 N.sub.2 O.sub.4 S                                                    409, M.sup.+ H, 100%                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (408)   (DCI/NH.sub.3)                                                                          2.40(3H, s),                                                                   3.87(3H, s),                                                                   4.18(2H, s),                                                                   7.00(2H, d),                                                                   7.16-7.43(8H, m)                                           64 C.sub.19 H.sub.16 N.sub.2 O.sub.2 S                                                    354, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (336)   12%; 337, M.sup.+ H,                                                                    3.65(2H, s),                                                          100%; 305, 30%                                                                          7.20-7.55(11H, m)                                                     (DCI/NH.sub.3)                                                      65 C.sub.18 H.sub.13 N.sub.3 O.sub.4                                                      336, MH.sup.+, 100%;                                                                    CDCl.sub.3, CF.sub.3 CO.sub.2 D                                                         C 67.45                                                                             67.44                                                                             67.44                                        (335)   353, MNH.sub.4.sup.+,                                                                   8.31(1H, d),                                                                            H 4.47                                                                              4.37                                                                              4.32                                                 20%; 306, 30%;                                                                          7.78(1H, m),                                                                            N 8.28                                                                              8.27                                                                              8.29                                                 291, 30% 7.65(1H, m),                                                          (DCI/NH.sub.3)                                                                          7.55-7.52(7H m),                                                               7.31(1H, s)                                                66 C.sub.24 H.sub.25 N.sub.3 O.sub.4                                                      437, MNH.sub.4.sup.+, 5%;                                                               d.sub.6 -DMSO                                                                           C 68.72                                                                             68.83                                                                             68.80                                        (419)   420, MH.sup.+, 6%;                                                                      1.40(9H, s),                                                                            H 6.01                                                                              5.89                                                                              5.85                                                 381, 17%; 364,                                                                          4.12(2H, d),                                                                            N 10.02                                                                             9.81                                                                              9.83                                                 100%; 318, 13%;                                                                         6.77(2H, d),                                                          303, 9%; 291,                                                                           7.22-7.56(9H, m)                                                      32%                                                                            (DCI/NH.sub.3)                                                      67 C.sub.20 H.sub.19 N.sub.3 O.sub.3                                                      350, MH.sup.+, 12%;                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (349)   349, M.sup.+, 13%;                                                                      3.92(3H, s),                                                          333, 100%                                                                               4.32(2H, s),                                                          (DCI/NH.sub.3)                                                                          7.05(2H, d),                                                                   7.24(2H),                                                                      7.45(2H, d),                                                                   7.52(4H, s)                                                68 C.sub.26 H.sub.28 N.sub.4 O.sub.5                                                      494, MNH.sub.4.sup.+,                                                                   d.sub.6 -DMSO                                                 (476)   10%; 477, MH.sup.+,                                                                     2.09(3H, s),                                                          18%; 476, M.sup.+,                                                                      2.10(9H, s),                                                          17%; 438, 22%;                                                                          4.12(2H, d),                                                          421, 100%; 405,                                                                         6.71(2H, d),                                                          9%; 375, 6%;                                                                            7.26(2H),                                                             360, 28% 7.49(4H, m),                                                          (DCI/NH.sub.3)                                                                          7.61(2H, d)                                                69 C.sub.19 H.sub.14 N.sub.2 O.sub.3 F.sub.2                                              357, 100%                                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 64.04                                                                             63.47                                                                             63.36                                        (356)   (DCI/NH.sub.3)                                                                          3.88(3H, s),                                                                            H 3.96                                                                              3.86                                                                              3.82                                                          6.90-7.20(4H, m),                                                                       N 7.86                                                                              7.79                                                                              7.77                                                          7.11(1H, s),                                                                   7.22(1H, s),                                                                   7.37-7.44(3H, m)                                           70 C.sub.20 H.sub.15 N.sub.2 O.sub.3 F.sub.3                                              389, 100; 406,                                                                          CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (388)   19%      3.90(3H, s),                                                          (DCI/NH.sub.3)                                                                          7.04(2H, d),                                                                   7.23(1H, s),                                                                   7.37-7.47(4H, m),                                                              7.55(1H, t),                                                                   7.62(1H, t),                                                                   7.80(1H, d)                                                71 C.sub.20 H.sub.16 N.sub.3 O.sub.3 F                                                             CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                               2.36(3H, s),                                                                   7.18-7.30(4H, m),                                                              7.40-7.50(4H, m),                                                              7.58(2H, d)                                                72 C.sub.20 H.sub.16 N.sub.3 O.sub.3 F                                                    383, 21%;                                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (365)   366, 100%;                                                                              2.36(3H, s),                                                          323, 12% 7.17-7.28(4H, m),                                                     (DCI/NH.sub.3)                                                                          7.41-7.49(4H, m)                                                               7.60(2H, d)                                                73 C.sub.21 H.sub.20 N.sub.2 O.sub.5                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.31                                                                             66.12                                                                             66.13                                                         3.90(6H, s),                                                                            H 5.30                                                                              5.25                                                                              5.22                                                          3.99(3H, s),                                                                            N 7.36                                                                              7.35                                                                              7.33                                                          6.60(1H, s),                                                                   7.01(2H, d,                                                                    J=6Hz),                                                                        7.19(2H, m),                                                                   7.30(1H, s),                                                                   7.32(1H, s),                                                                   7.40(2H, d,                                                                    J=6Hz)                                                     74 C.sub.18 H.sub.13 N.sub.3 O.sub.4                                                      336, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 64.48                                                                             64.55                                                                             64.57                                                                             3250,                                     (335)   353, MNH.sub.4.sup.+,                                                                   8.35(d, 2H),                                                                            H 3.91                                                                              3.90                                                                              3.89                                                                              1690,                                             20%; 306, 30%;                                                                          7.62(d, 2H),                                                                            N 12.53                                                                             12.41                                                                             12.41                                                                             1620,                                             291, 30% 7.55-7.42(m, 5H),   1570,                                             (DCI/NH.sub.3)                                                                          7.36(s, 1H),        1420, 1370                                                 7.28(s, 1H)                                                75 C.sub.23 H.sub.25 N.sub.3 O.sub.3                                                      392, MH.sup.+, 100%                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 70.57                                                                             70.28                                                                             70.46                                                (DCI/NH.sub.3)                                                                          2.30(2H, m),                                                                            H 6.44                                                                              6.33                                                                              6.36                                                          3.01(6H, s),                                                                            N 10.73                                                                             10.59                                                                             10.68                                                         3.43(2H, m),                                                                   4.15(2H, m),                                                                   6.96(2H, d,                                                                    J=8Hz),                                                                        7.23(1H, s),                                                                   7.40-7.55(8H, m)                                           76 C.sub.21 H.sub.16 N.sub.2 O.sub.3 S                                                    396, MNH.sub.4.sup..sup.+, 4%;                                                          CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.65                                                                             66.79                                                                             66.82                                                379, MH.sup.+, 100%                                                                     7.53-7.34(10H,                                                                          H 4.79                                                                              4.69                                                                              4.71                                                 (DCI/NH.sub.3)                                                                          m),      N 7.40                                                                              7.41                                                                              7.41                                                          7.21(1H, s),                                                                   4.18(2H, s),                                                                   2.42(3H, s)                                                77 C.sub.20 H.sub.15 N.sub.3 O.sub.3 S.sub.2                                              401, 100%;                                                                              CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 62.66                                                                             62.65                                                                             62.63                                        (383)   384, 75% 2.37(3H, s),                                                                            H 3.94                                                                              4.11                                                                              4.11                                                 (DCI/NH.sub.3)                                                                          6.90-7.05(2H, m),                                                                       N 10.96                                                                             11.32                                                                             11.33                                                         7.18(1H, s),                                                                   7.27(1H, s),                                                                   7.39-7.50(3H, m),                                                              7.60(2H, d)                                                78 C.sub.21 H.sub.16 N.sub.3 O.sub.3 F.sub.3                                              416, 100%;                                                                              CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 60.72                                                                             60.08                                                                             60.11                                        (415)   433, 100%                                                                               2.37(3H, s),                                                                            H 3.88                                                                              4.14                                                                              4.15                                                 (DCI/NH.sub.3)                                                                          7.22(1H, s),                                                                            N 10.12                                                                             10.84                                                                             10.87                                                         7.42-7.49(4H, m),                                                              7.56-7.70(4H, m),                                                              7.32(1H, d)                                                79 C.sub.20 H.sub.16 N.sub.3 O.sub.3 Br                                                   426:428, CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 56.35                                                                             56.65                                                                             56.79                                        (426 ± 1)                                                                           (41:41)%;                                                                               2.36(3H, s),                                                                            H 3.78                                                                              3.92                                                                              3.84                                                 443:445, 7.22(1H, s),                                                                            N 9.86                                                                              9.97                                                                              10.01                                                (100:100)%                                                                              7.29-7.35(2H, m),                                                     (DCI/NH.sub.3)                                                                          7.38-7.49(4H, m),                                                              7.60(2H, d),                                                                   7.72(1H, d)                                                80 C.sub.20 H.sub.17 N.sub.3 O.sub.4                                                      351, 10%, MH.sup.+,                                                                     d.sub.6 -DMSO                                                                           C 66.11                                                                             65.57                                                                             65.49                                        (363)   364      7.98(1H, bs),                                                                           H 4.72                                                                              4.71                                                                              4.71                                                 (DCI/NH.sub.3)                                                                          7.90(2H, d),                                                                            N 11.56                                                                             11.32                                                                             11.31                                                         7.60(2H, d),                                                                   7.55(2H, d),                                                                   7.40(1H, bs),                                                                  7.00(2H, d),                                                                   6.78(2H, m),                                                                   3.79(3H, s)                                                81 C.sub.24 H.sub.24 N.sub.2 O.sub.5                                                      336, 20%; 351,                                                                          CDCl.sub.3 +CF.sub.3 CO.sub.2 D                               (420)   15%; 379, 25%;                                                                          7.48(2H, d),                                                          421, MH.sup.+, 100%,                                                                    7.45(2H, d),                                                          MNH.sub.4.sup.+, 438, 10%                                                               7.20(4H, m),                                                          (DCI/NH.sub.3)                                                                          7.02(2H, d),                                                                   3.90(3H, s),                                                                   1.38(9H, s)                                                82 C.sub.25 H.sub.25 N.sub.3 O.sub.5                                                      363, 25%; 406,                                                                          CDCl.sub.3 +CF.sub.3 CO.sub.2 D                               (447)   15%; 448, MH.sup.+                                                                      7.62(2H, d),                                                          100%     7.48(4H, m),                                                          (DCI/NH.sub.3)                                                                          7.25(2H, d),                                                                   7.20(2H, d),                                                                   2.35(3H, s),                                                                   1.40(9H, s)                                                83 C.sub.21 H.sub.19 N.sub.3 O.sub.5                                                      411, MNH.sub.4.sup.+,                                                                   d.sub.6 -DMSO                                                         10%; 394, MH.sup.+,                                                                     3.68(3H, s),                                                          100%; 362, 57%                                                                          3.80(3H, s),                                                          (DCI/NH.sub.3)                                                                          6.57(1H, s),                                                                   6.60(1H, s),                                                                   6.95(2H, d,                                                                    J=7Hz),                                                                        7.47(2H, d,                                                                    J=7Hz),                                                                        7.67(4H, m),                                                                   9.68(1H, br.s),                                                                9.78(2H, br.s)                                             84 C.sub.19 H.sub.15 N.sub.2 O.sub.4 Cl                                                   371, MH.sup.+, 100%;                                                                    d.sub.6 -DMSO                                                 (370/372)                                                                              373, 30%; 388,                                                                          10.08(s, 2H),                                                         MNH.sub.4.sup.+, 45%                                                                    7.52(d, 2H),                                                          (DCI/NH.sub.3)                                                                          7.45(d, 1H),                                                                   6.98(d, 2H),                                                                   6.90(d, 1H),                                                                   6.80(dd, 1H),                                                                  6.76(s, 1H),                                                                   6.74(s, 1H),                                                                   3.79(s, 3H)                                                85 C.sub.18 H.sub.13 N.sub.2 O.sub.3 Cl                                                   341, MH.sup.+, 100%;                                                                    d.sub.6 -DMSO                                                 (340/342)                                                                              343, 30%; 358,                                                                          8.98(s, 1H),                                                          MNH.sub.4.sup.+, 5%; 305,                                                               8.91(s, 1H),                                                          50%      8.88(s, 1H),                                                          (DCI/NH.sub.3)                                                                          7.58(d, 2H),                                                                   7.50(d, 1H),                                                                   7.45(m, 2H),                                                                   7.37(m, 1H),                                                                   6.94(d, 1H),                                                                   6.83(dd, 1H),                                                                  6.80(s, 1H),                                                                   6.79(s, 1H)                                                86 C.sub.22 H.sub.22 N.sub.4 O.sub.3                                                      391, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 67.68                                                                             66.97                                                                             66.70                                        (390)   408, MNH.sub.4.sup.+, 5%                                                                7.66-7.58(m, 6H),                                                                       H 5.68                                                                              5.64                                                                              5.50                                                 (DCI/NH.sub.3)                                                                          7.46(2H),                                                                               N 14.35                                                                             14.35                                                                             14.15                                                         7.24(2H),                                                                      3.35(s, 6H),                                                                   2.35(s, 3H)                                                87 C.sub.23 H.sub.21 N.sub.3 O.sub.6                                                      453, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                      30%; 436, MH.sup.+,                                                                     2.32(3H, s),                                                          100%     3.92(3H, s),                                                          (DCI/NH.sub.3)                                                                          4.89(2H, s),                                                                   7.03(2H, d,                                                                    J=6Hz),                                                                        7.24(1H, s),                                                                   7.28(1H, s),                                                                   7.46(2H, d,                                                                    J=6Hz),                                                                        7.50(2H, d,                                                                    J=7Hz),                                                                        7.64(2H, d,                                                                    J=7Hz)                                                     88 C.sub.21 H.sub.19 N.sub.3 O.sub.5                                                      411, MNH.sub.4.sup.+,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                      51%; 394, MH.sup.+,                                                                     3.92(3H, s),                                                          100%;    4.57(2H, br.s),                                                       336, 52% 7.08(2H, d,                                                           (DCI/NH.sub.3)                                                                          J=7Hz),                                                                        7.25(1H, s),                                                                   7.28(1H, s),                                                                   7.49(2H, d,                                                                    J=7Hz),                                                                        7.50(2H, d,                                                                    J=7Hz),                                                                        7.70(2H, d,                                                                    J=7Hz)                                                     89 C.sub.24 H.sub.21 N.sub.3 O.sub.2                                                      384, MH.sup.+, 100%;                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 75.18                                                                             74.92                                                                             74.81                                        (383)   356, 5%; 296,                                                                           8.26(d, 1H),                                                                            H 5.52                                                                              5.50                                                                              5.52                                                 5%       8.07(d, 1H),                                                                            N 10.96                                                                             10.99                                                                             11.02                                                (DCI/NH.sub.3)                                                                          7.86(m, 1H),                                                                   7.78(d, 1H),                                                                   7.74(d, 1H),                                                                   7.68(m, 2H),                                                                   7.55-7.45(m, 5H),                                                              7.29(s, 1H),                                                                   3.55(s, 6H)                                                90 C.sub.20 H.sub.18 N.sub.2 O.sub.4                                                      351, M.sup.+ +1, 100%                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (350)   (EI)     3.90(3H, s, OMe),                                                              3.95(3H, s, OMe),                                                              6.90-7.50(10H, m)                                          91 C.sub.21 H.sub.20 N.sub.2 O.sub.5                                                      381, 100%                                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.31                                                                             66.40                                                                             66.20                                        (380)   (EI)     3.85(3H, s, OMe),                                                                       H 5.30                                                                              5.27                                                                              5.16                                                          3.90(3H, s, OMe),                                                                       N 7.36                                                                              7.34                                                                              7.36                                                          3.95(3H, s, OMe),                                                              6.90-7.45(9H, m)                                           92 C.sub.22 H.sub.21 N.sub.3 O.sub.5                                                      425, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 64.86                                                                             64.27                                                                             64.13                                        (407)   25%; 408, MH.sup.+,                                                                     2.35(3H, s, Ac),                                                                        H 5.20                                                                              5.15                                                                              5.15                                                 100%     3.90(3H, s, OMe),                                                                       N 10.31                                                                             10.54                                                                             10.53                                                (DCI/NH.sub.3)                                                                          3.95(3H, s, OMe),                                                              6.90-7.60(9H, m)                                           93 C.sub.21 H.sub.18 N.sub.2 O.sub.5                                                      396, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 66.66                                                                             66.77                                                                             66.83                                        (378)   15%; 379, MH.sup.+,                                                                     3.90(3H, s, Me),                                                                        H 4.79                                                                              4.80                                                                              4.82                                                 100%     4.75(2H, s, CH.sub.2),                                                                  N 7.40                                                                              7.76                                                                              7.79                                                 (DCI/NH.sub.3)                                                                          6.95-7.50(11H, m)                                          94 C.sub.25 H.sub.25 H.sub.3 O.sub.5                                                      465, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 67.10                                                                             66.81                                                                             66.96                                        (447)   15%; 448, MH.sup.+,                                                                     2.00-2.05(2H, m),                                                                       H 5.63                                                                              5.44                                                                              5.42                                                 100%; 416, M.sup.+ --                                                                   2.43-2.50(4H, m),                                                                       N 9.39                                                                              9.46                                                                              9.50                                                 OMe, 20% 3.75(3H, s, Me),                                                      (DCI/NH.sub.3)                                                                          4.50(2H, s,                                                                    CH.sub.2 Ar),                                                                  7.25-7.50(11H, m)                                          95 C.sub.27 H.sub.29 N.sub.3 O.sub.5                                                      493(M.sup.+ NH.sub.4,                                                                   CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 68.20                                                                             68.13                                                                             68.28                                        (475)   10%; 476, MH.sup.+,                                                                     1.30(3H, t, Me),                                                                        H 6.15                                                                              5.95                                                                              6.00                                                 16%;     1.70-1.75(4H, m),                                                                       N 8.84                                                                              8.88                                                                              8.91                                                 (DCI/NH.sub.3)                                                                          2.40-2.45(4H, m),                                                              4.20(2H, q),                                                                   4.53(2H, s),                                                                   7.25-7.50(11H, m)                                          96 C.sub.24 H.sub.24 N.sub.2 O.sub.5                                                      421, MH.sup.+, 100%                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                      (DCI/NH.sub.3)                                                                          1.88(4H, m),                                                                   2.50(2H, m),                                                                   3.77(3H, s),                                                                   4.04(2H, m),                                                                   7.00(2H, d,                                                                    J=8Hz),                                                                        7.21(1H, s),                                                                   7.38-7.53(8H, m)                                           97 C.sub.23 H.sub.22 N.sub.2 O.sub.5                                                      424, MNH.sub.4.sup.+, 2%;                                                               CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                      407, MH.sup.+, 100%;                                                                    1.92(4H, m),                                                          291, 71% 2.55(2H, m),                                                          (DCI/NH.sub.3)                                                                          4.09(2H, m),                                                                   7.03(2H, d,                                                                    J=8Hz), 7.24(1H,                                                               s),                                                                            7.29(1H, s),                                                                   7.39-7.55(7H, m)                                           98 C.sub.23 H.sub.26 N.sub.3 O.sub.3 Cl                                                   392, (M--Cl).sup.+,                                                                     d.sub.6 -DMSO                                                         100%     2.15(2H, m),                                                          (ESI + QIMS)                                                                            3.20(2H, m),                                                                   3.29(6H, s),                                                                   4.12(2H, m),                                                                   6.77(1H, s),                                                                   6.78(1H, s),                                                                   7.00(2H, d,                                                                    J=8Hz),                                                                        7.32(1H, m),                                                                   7.40(2H, m),                                                                   7.55(4H, m),                                                                   10.13(2H, br.s)                                            99 C.sub.22 H.sub.24 N.sub.3 O.sub.3 Cl                                                   430, 7%; d.sub.6 -DMSO                                                         412, 5%; 2.85(6H, s,                                                           478, 100%                                                                               2×Me),                                                                   3.50(2H, t, CH.sub.2),                                                         4.40(2H, t, CH.sub.2),                                                         6.75-7.55(11H,                                                                 m),                                                                            10.15(2H, br.s,                                                                2×NH),                                                                   10.75(1H,                                                                      v.br.s., NH)                                               100                                                                               C.sub.26 H.sub.27 N.sub.3 O.sub.6                                                      495, M.sup.+ NH.sub.4,                                                                  CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (477)   13%;     2.00-2.17(2H, m),                                                     478, MH.sup.+, 100%;                                                                    2.45-2.52(4H, m),                                                     446, 15% 3.75(3H, s, Me),                                                      (DCI/NH.sub.3)                                                                          3.88(3H, s, Me),                                                               4.50(2H, s),                                                                   7.00-7.40(10H, m)                                          101                                                                               C.sub.20 H.sub.16 N.sub.2 O.sub.5                                                      382, M.sup.+ NH.sub.4,                                                                  d.sub.6 -DMSO                                                 (364)   80%; 365, M.sup.+ +1,                                                                   4.70(2H, s,                                                           100%     OCH.sub.2),                                                           (DCI/NH.sub.3)                                                                          6.75-7.55(11H,                                                                 m),                                                                            10.12(1H, br.s.,                                                               NH),                                                                           10.17(1H, br.s.,                                                               NH)                                                        102                                                                               C.sub.22 H.sub.23 N.sub.3 O.sub.3                                                      378, MH.sup.+, 100%                                                                     CDCl.sub.3 + CF.sub.3 CO.sub.2 D                              (377)   (DCI/NH.sub.3)                                                                          3.10(6H, s,                                                                    2×Me),                                                                   3.65(2H, t, CH.sub.2),                                                         4.40(2H, t, CH.sub.2),                                                         6.95-7.50(11H, m)                                          103                                                                               C.sub.19 H.sub.15 N.sub.2 O.sub.3 F                                                    339 100% CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 67.45                                                                             67.44                                                                             67.44                                        (338)   (DCI/NH.sub.3)                                                                          3.91(3H, s),                                                                            H 4.47                                                                              4.37                                                                              4.32                                                          7.03(2H, d),                                                                            N 8.28                                                                              8.27                                                                              8.29                                                          7.16-7.30(4H, m),                                                              7.39-7.48(4H, m)                                           104                                                                               C.sub.21 H.sub.19 N.sub.3 O.sub.4                                                      395, MNH.sup.+.sub.4,                                                                   d.sub.6 -DMSO                                                 (377)   32%; 378, MH.sup.+,                                                                     2.04(3H, s),                                                          38%      4.51(2H, d),                                                          (DCI/NH.sub.3)                                                                          5.18(1H, t,),                                                                  6.72(1H, s),                                                                   6.78(1H, s),                                                                   7.36(2H, d),                                                                   7.50(4H, m),                                                                   7.62(2H, d)                                                105                                                                               C.sub.19 H.sub.13 O.sub.2 N.sub.3                                                      316, MH.sup.+, 100%,                                                                    CDCl.sub.3 + CF.sub.3 CO.sub.2 D                                                        C 72.37                                                                             72.26                                                                             72.15                                                201, 53% 7.25(1H, s),                                                                            H 4.16                                                                              4.21                                                                              4.20                                                 (DCI/NH.sub.3)                                                                          7.38(1H, s),                                                                            N 13.33                                                                             13.21                                                                             13.16                                                         7.43-7.60(5H, m),                                                              7.61(2H, d,                                                                    J=7Hz),                                                                        7.85(2H, d,                                                                    J=7Hz)                                                     __________________________________________________________________________ 

We claim:
 1. A compound selected from the group consisting of a diketopiperazine of formula (A): ##STR13## wherein R₈ is NHAc wherein Ac is acetyl; R₁ is H or halogen; R₂ is H; R₃ is halogen, C₁ -C₆ alkoxy, --N(R¹¹ R¹²) or --NHCOOR¹³ ; and each of R¹¹ and R¹² is independently H or C₁ -C₆ alkyl and R¹³ is C₁ -C₆ alkyl; R₁ is H; R₅ is halogen or CF₃ ; R₆, R₇, R₈ and R₁₀ are H; and the pharmaceutically acceptable salts thereof.
 2. A compound selected from the group consisting of a diketopiperazine of formula (A): ##STR14## wherein R₁, R₆, R₇, R₈, R₉ and R₁₀ are H; R₂ is H and R₃ is --CH₂ SR¹¹, --CH₂ SCOR¹¹, --NHCO(CH₂)_(n) CO₂ R¹¹, --O(CH₂)_(n) CO₂ R¹¹, --O(CH₂)_(n) N(R¹¹ R¹²), or R₂ is --CH₂ SCOR¹³ or --CH₂ SR¹¹ and each of R¹¹ and R¹² is independently H or C₁ -C₆ alkyl and R¹³ is C₁ -C₆ alkyl; and R₃ is H; and R₄ and R₅ are both H or form, together with the carbon atoms to which they are attached, a benzene ring; and the pharmaceutically acceptable salts thereof.
 3. A pharmaceutical or veterinary composition comprising a pharmaceutically or veterinarily acceptable carrier or diluent and, as an active principle, a compound as claimed in claim
 1. 4. A pharmaceutical or veterinary composition comprising a pharmaceutically or veterinarily acceptable carrier or diluent and, as an active principle, a compound as claimed in claim
 2. 